U.S. patent application number 13/714933 was filed with the patent office on 2013-07-11 for non-lithotripsic kidney-stone therapy.
This patent application is currently assigned to The General Hospital Corporation. The applicant listed for this patent is The General Hospital Corporation, Pluromed, Inc.. Invention is credited to W. Scott McDougal, Dianne E. Sacco, Alexander Schwarz, Jean-Marie Vogel.
Application Number | 20130178866 13/714933 |
Document ID | / |
Family ID | 36928585 |
Filed Date | 2013-07-11 |
United States Patent
Application |
20130178866 |
Kind Code |
A1 |
McDougal; W. Scott ; et
al. |
July 11, 2013 |
Non-Lithotripsic Kidney-Stone Therapy
Abstract
One aspect of the present invention relates to a method of using
peristalsis to force a polymer plug through a mammalian lumen,
thereby removing any calculi and/or calculi fragments present in
the lumen. In one embodiment, the method is used as an alternative
to conventional lithotripsy. In another embodiment, the method is
used in conjunction with lithotripsy, thereby removing the small
calculi fragments that result from such procedures.
Inventors: |
McDougal; W. Scott; (Boston,
MA) ; Sacco; Dianne E.; (Boston, MA) ;
Schwarz; Alexander; (Cambridge, MA) ; Vogel;
Jean-Marie; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pluromed, Inc.;
The General Hospital Corporation; |
Cambridge
Boston |
MA
MA |
US
US |
|
|
Assignee: |
The General Hospital
Corporation
Boston
MA
Pluromed, Inc.
Cambridge
MA
|
Family ID: |
36928585 |
Appl. No.: |
13/714933 |
Filed: |
December 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11412407 |
Apr 27, 2006 |
8361455 |
|
|
13714933 |
|
|
|
|
60676757 |
May 2, 2005 |
|
|
|
Current U.S.
Class: |
606/127 |
Current CPC
Class: |
A61B 17/32056 20130101;
A61P 1/16 20180101; A61L 24/046 20130101; A61K 9/0019 20130101;
A61K 47/10 20130101; A61K 47/36 20130101; A61L 24/046 20130101;
A61B 2017/00818 20130101; A61K 49/0002 20130101; A61P 13/04
20180101; A61B 2017/00853 20130101; A61B 2017/00849 20130101; A61B
2018/00511 20130101; A61P 1/18 20180101; A61L 24/001 20130101; A61P
13/12 20180101; A61B 2017/22037 20130101; A61B 2018/005 20130101;
A61B 17/22 20130101; A61B 2017/22082 20130101; A61L 2400/06
20130101; C08L 71/02 20130101 |
Class at
Publication: |
606/127 |
International
Class: |
A61B 17/22 20060101
A61B017/22 |
Claims
1. A method of treating lithiasis, comprising the steps of:
injecting into a lumen of a mammal at a first distance upstream
from a calculi a first composition comprising between 12 and 25
weight percent of an inverse thermosensitive polymer selected from
a block copolymer, random copolymer, graft polymer, or branched
copolymer, wherein said first composition does not initially
contact said calculi; thereby forming a polymer plug; and removing
the calculi from the lumen by movement of the polymer plug by
peristalsis to traverse said lumen, thereby forcing said calculi
from said lumen.
2. The method of claim 1, further comprising injecting into said
lumen a second composition at a second distance upstream from said
calculi wherein said second composition does not contact said
calculi.
3. The method of claim 1, wherein said first distance is between
about 1 cm and about 5 cm upstream of said calculi.
4. The method of claim 2, wherein the distance between said first
distance and said second distance is less than about 3 mm.
5. The method of claim 1, wherein said first composition is
injected into said lumen through a percutaneous access device.
6. The method of claim 1, wherein said lumen is or is a portion of
a kidney, gall bladder, ureter, urinary bladder, pancreas, salivary
gland, small intestine, or large intestine.
7. The method of claim 1, wherein said lumen is or is a portion of
a ureter or kidney.
8. The method of claim 1, wherein said calculi is a kidney stone,
pancreatic stone, salivary stone, or biliary stone.
9. The method of claim 1, wherein said calculi is a kidney
stone.
10. A method of treating lithiasis, comprising the steps of:
injecting into a lumen of a human at a first distance upstream from
a calculi a first composition comprising an inverse thermosensitive
polymer, wherein said first composition does not initially contact
said calculi; thereby forming a polymer plug; injecting into said
lumen a second composition at a second distance upstream from said
calculi wherein said second composition does not contact said
calculi; and removing the calculi from the lumen by movement of the
polymer plug by peristalsis to traverse said lumen, thereby forcing
said calculi from said lumen.
11. The method of claim 10, wherein said second composition
comprises a contrast-enhancing agent.
12. The method of claim 10, 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.
13. The method of claim 10, wherein said inverse thermosensitive
polymer is an optionally purified poloxamer or poloxamine.
14. The method of claim 10, wherein said inverse thermosensitive
polymer is optionally purified and selected from the group
consisting of poloxamine 1107, poloxamine 1307, poloxamer 338 and
poloxamer 407.
15. The method of claim 10, wherein said inverse thermosensitive
polymer is an optionally purified poloxamer 407.
16. The method of claim 10, wherein said first composition has a
transition temperature of between about 10.degree. C. and
40.degree. C.
17. The method of claim 10, wherein said lumen is or is a portion
of a kidney, gall bladder, ureter, urinary bladder, pancreas,
salivary gland, small intestine or large intestine.
18. The method of claim 10, wherein said lumen is or is a portion
of a ureter or kidney.
19. The method of claim 10, wherein said calculi is a kidney stone,
pancreatic stone, salivary stone, or biliary stone.
20. The method of claim 1, wherein the polymer plug is non-tissue
adhesive.
21. The method of claim 2, wherein the second composition comprises
a cross-linker solution.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/412,407, filed Apr. 27, 2006, which claims the benefit of
U.S. Provisional Application No. 60/676,757, filed on May 2,
2005.
[0002] The entire teachings of the above applications are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0003] Lithiasis is a common human ailment characterized by calculi
or "stones" formed within a passage of the human body. While stones
have been documented in just about every passage within the body,
kidney stones (nephrolithiasis) and gallstones (cholelithiasis)
remain the most common. Regardless of its location, however, a
stone is typically an extremely hard and unyielding mass which
blocks the passage (e.g., lumen) in which it presents.
[0004] Calculi or stones in the urinary tract or kidneys usually
arise because of the breakdown of a delicate balance in the body.
Specifically, the kidneys must conserve water to function, but they
must excrete materials that have a low solubility. These opposing
requirements must be balanced during adaptation to diet, climate
and activity. The problem is mitigated to some degree because urine
contains substances that inhibit crystallization of stone-forming
minerals. However, when urine becomes supersaturated with insoluble
materials, because excretion rates are excessive and/or because
water conservation is extreme, crystals form and may grow and
aggregate to form a stone.
[0005] Although small crystals are readily voided from the kidney
with urine, the larger stones frequently become dislodged from the
kidney and enter the ureter or occlude the uretero-pelvic junction,
causing obstruction and pain. Although some stones can ultimately
traverse the ureter, their passage typically produces pain and
bleeding. Usually, the pain is so severe that narcotic drugs are
needed for its control.
[0006] Removal of stones from the kidneys or urinary tract can be
effected medically, mechanically or surgically. A well-known
surgical approach involves passing a flexible basket in a
retrograde manner up the ureter from the bladder, and using the
basket to capture the stones. However, the baskets require
post-capture removal and only work well for medium-sized stones.
Surgery has also been used to remove kidney stones, especially
so-called staghorn stones which get lodged in the ureter.
[0007] Another surgical technique, percutaneous ultrasonic
lithotripsy, requires the passage of a rigid cystoscopy-like
instrument in the renal pelvis through a small incision in the
flank whereupon stones are broken up by a small ultrasound
transducer and then removed directly. Another surgical technique is
laser lithotripsy via a ureteroscope. All of these procedures,
which can be quite painful, are elaborate and expensive, and they
do not always result in complete removal of the stones and
fragments. One non-invasive technique, known as extracorporeal
lithotripsy, entails transmission of high-intensity shock waves
from outside the body to fragment the stones within the body. The
resulting stone fragments are then voided with urine.
[0008] Stents have also been used to decompress ureteral
obstructions, ensuring that urine drains from the kidney to the
bladder. It was recognized that placement of a stent within the
ureter could help small stones and stone fragments to transit the
ureter. In a typical procedure involving a stent, a guide wire is
passed through the ureter to the renal pelvis. A hollow, flexible,
cylindrical stent is then advanced with a pusher over the guide
wire. The guide wire and pusher are then extracted from the stent
and the body, leaving an open lumen for urine to pass through.
However, because the lumen defined by the cylindrical stent is even
smaller than the ureter itself, all but the smallest stones and
sludge are precluded from passing through. In many cases, stone
fragments often block the open stent passageway.
SUMMARY OF THE INVENTION
[0009] One aspect of the present invention provides an approach to
the treatment of lithiasis. In one embodiment, the instant
invention provides a method of using peristalsis to force a polymer
plug through a mammalian lumen, thereby removing any calculi and/or
calculi fragments present in the lumen. In one embodiment this
method is used as an alternative to conventional lithotripsy. In
another embodiment this method is used subsequent to lithotripsy,
removing the small fragments that result from such procedures. In
certain embodiments, the polymer plug is generated in situ by one
or more physical phenomena, such as temperature, pH change and/or
ionic interactions. In certain embodiments the polymer plug rapidly
dissolves after passing through the lumen.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 depicts the deployment of a catheter into a lumen
containing a calculi.
[0011] FIG. 2 depicts one embodiment of the deployment of a polymer
in a lumen at a position upstream from a calculi.
[0012] FIG. 3 depicts the position of the polymer plug and calculi
before peristaltic motion.
[0013] FIG. 4 depicts the effect of peristalsis (i.e. the movement
of the polymer plug towards the outlet of the lumen and the
resulting expulsion of the calculi).
[0014] FIG. 5 depicts dissolution times under static conditions for
purified poloxamer 407 as function of concentration (see Example
3).
DETAILED DESCRIPTION OF THE INVENTION
[0015] One aspect of the present invention provides an approach to
the treatment of lithiasis. Importantly, the present invention
mitigates the risk of damage to surrounding body tissue when
removing a calculi (e.g., biological concretions such as urinary,
biliary, and pancreatic stones) which obstructs or may otherwise be
present within a body's anatomical lumen. Remarkably, the present
invention improves significantly the treatment of lithiasis, while
simultaneously reducing the risk of tissue damage and decreasing
the procedure time.
[0016] In one embodiment, the instant invention provides a method
of using a non-tissue adhesive polymer plug to partially or
completely occlude a lumen and using the plug to remove calculi
and/or calculi fragments from the lumen through the passage of the
polymer plug through the lumen due to the natural action of
peristalsis on the polymer plug. In one embodiment the method is
used as an alternative to conventional lithotripsy. In another
embodiment the method is used subsequent to lithotripsy, to remove
the small fragments that result from such procedures. In certain
embodiments the polymer plug is generated in situ by one or more
physical phenomena, such as temperature, pH changes and/or ionic
interactions. In some of these embodiments a dual lumen catheter is
utilized to inject two solutions proximal to the stone, the mixing
of said solutions causing a polymer plug to form. In certain
embodiments the polymers used in the methods of the invention are
inverse thermosensitive polymers. In other embodiment, gel
formation due to ionic charges may be used to form a polymer plug.
In certain embodiments the polymer plug rapidly dissolves, e.g., in
the bladder, after being passed through the lumen.
DEFINITIONS
[0017] For convenience, certain terms employed in the
specification, exemplification, and appended claims are collected
here.
[0018] The articles "a" and "an" are used herein to refer to one or
to more than one
[0019] (i.e., to at least one) of the grammatical object of the
article. By way of example, "an element" means one element or more
than one element.
[0020] The terms "reversibly gelling" and "inverse thermosensitive"
refer to the property of a polymer wherein gelation takes place
upon an increase in temperature, rather than a decrease in
temperature.
[0021] The term "transition temperature" refers to the temperature
or temperature range at which gelation of an inverse
thermosensitive polymer occurs.
[0022] 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.
[0023] 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.
[0024] As used herein, "crosslinking" 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.
[0025] 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. The
term "non-tissue adhesive", as used herein denotes a substance
(e.g. a polymer plug) does not adhere to biological tissue.
[0026] The term "poloxamer" denotes a symmetrical block copolymer,
consisting of a core of PPG polyoxyethylated at both of 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.
[0027] 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.
[0028] The term "inverse thermosensitive polymer" as used herein
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
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
Bull. Korean Chem. Soc. 2002, 23, 549-554.
[0029] "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).
[0030] "Sodium alginate" and "potassium alginate" are salts of
alginic acid. For example, "potassium alginate" is shown below:
##STR00002##
[0031] "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.
[0032] Carboxymethylcellulose (CMC) is a polymer derived from
natural cellulose. Unlike cellulose, CMC is highly water-soluble.
The CMC structure is based on the b-(1.RTM. 4)-D-glucopyranose
polymer of cellulose. Different preparations may have different
degrees of substitution, but it is generally in the range 0.6-0.95
derivatives per monomer unit, as shown below: acc
##STR00003##
[0033] 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.
[0034] "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 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##
[0035] In certain embodiments polyvinyl alcohol (PVA) is a
synthetic resin produced by polymerisation 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.
[0036] 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##
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] The terms "calculi" and "calculus" denote one or more masses
or nodules of solid matter formed by growing together, by
congelation, condensation, coagulation, induration, etc. Common
synonyms, for example, are concretions, stones, clots, tones or
lumps. Often, in an organism a concretion is a hard lump of mineral
salts found in a hollow organ or duct. In one embodiment,
concretion refers to stone-like objects found within an organ
(e.g., the kidneys) of an organism.
[0043] 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 small intestine or a large intestine (i.e., an
opening, space, or cavity in a biological system). A lumen has an
"inlet" and an "outlet" based on the direction of the flow of
materials through the lumen. As used here "upstream" from a given
object in a lumen means between said object and the inlet of the
lumen; "downstream" from a given object in a lumen means between
said object and the outlet of the lumen.
[0044] "Peristalsis" as used herein refers to a series of
coordinated, rhythmic muscle contractions. For example, it is an
automatic and vital process that moves food through the digestive
tract, urine from the kidneys through the ureters into the bladder,
and bile from the gallbladder into the duodenum. Peristalsis moves
material in a lumen towards the outlet of the lumen.
[0045] "Lithotripsy" as used herein refers to any procedure,
surgery or technique that fragments or breaks up a stone.
[0046] "Lithiasis" as used herein refers to a common human ailment
characterized by calculi or "stones" formed within a passage or
lumen of a human.
Calculi
[0047] Calculi can develop in parts of the body, such as in the
kidneys, pancreas, ureter and gallbladder. It is not uncommon for
biological calculi to be referred to as stones, especially when
they are composed of mineral salts. For example, calculi formed in
the biliary system are called gallstones. Those that form in the
bladder are often known as vesical calculi or bladder stones.
Calculi occurring in the kidney are often called kidney stones.
Calculi can also occur in the ureter; there they are usually the
result of the incomplete passage of a calculi originating in a
kidney. It is also possible to observe a calculi in a salivary duct
or gland.
[0048] There are four main types of calculi observed biologically.
The majority of calculi, about 75%, are calcium-containing,
composed of calcium oxalate, sometimes mixed with calcium
phosphate. Another 15% are composed of magnesium ammonium
phosphate; these calculi are often referred to as "triple stones"
or struvite stones. The bulk of the remaining stones are made up of
uric acid or cystine (Cys-Cys). As mentioned above, when calculi
are too large to pass spontaneously, medical intervention is often
needed.
Polymers of the Invention
[0049] In certain embodiments a polymer plug is generated in situ
by one or more physical phenomena, such as temperature, pH changes
and/or ionic interactions. In other embodiment, the polymers used
in a method of the invention are crosslinkable polymers. In certain
embodiments the polymer plug generate in situ is non-tissue
adhesive.
[0050] In one embodiment two solutions, a polymer solution and a
crosslinker solution, are injected separately (e.g., through a dual
lumen catheter) into a biological lumen wherein they gel, forming a
polymer plug. Said polymer solution may comprise an anionic
polymer, a cationic polymer or a non-ionically crosslinkable
polymer. Such polymers may comprise 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 to form a
polymer plug 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).
[0051] In addition, in certain embodiments, the polymer plugs of
the invention may be formed from an aqueous solution of one or more
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.
[0052] In general, the inverse thermosensitive polymers used in the
methods of the invention, which become a gel at or about body
temperature, can be injected into a patient's body in a liquid
form. The injected material upon reaching body temperature
undergoes a transition from a liquid to a gel. The inverse
thermosensitive 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. Also, the inverse thermosensitive polymer can
include a therapeutic agent.
[0053] The molecular weight of the inverse thermosensitive polymer
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 polymer (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.
[0054] The pH of the inverse thermosensitive polymer formulation
administered to the 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.
[0055] Suitable inverse thermosensitive polymers include
polyoxyethylene-polyoxypropylene (PEO-PPO) block copolymers. Two
examples are Pluronic.RTM. F127 and F108, which are PEO-PPO block
copolymers with molecular weights of 12,600 and 14,600,
respectively. Each of these compounds is available from BASF of
Mount Olive, N.J. Pluronic.RTM. F108 at 12-25% concentration in
phosphate buffered saline (PBS) is an example of a suitable inverse
thermosensitive polymeric material. Pluronic.RTM. acid F127 at
12-25% concentration in PBS is another example of a suitable
material. Low concentrations of dye (such as crystal violet),
hormones, therapeutic agents, fillers, and antibiotics can be added
to the inverse thermosensitive polymer. In general, other
biocompatible, biodegradable PEO-PPO block copolymers that exist as
a gel at body temperature and a liquid at below body temperature
may also be used according to the present invention.
[0056] Notably, 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 their
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).
[0057] The average molecular weights of the poloxamers 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 polymer.
[0058] 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.
[0059] 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. In certain
embodiments, a purified poloxamer or poloxamine has a
polydispersity index from about 1.1 to about 1.0.
[0060] 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.
[0061] 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. No. 5,523,492 and U.S. Pat. No.
5,696,298; both hereby incorporated by reference).
[0062] 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.
[0063] 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.
[0064] In a preferred embodiment, the polymers used are block
polymers such as polyoxyethylene-polyoxypropylene (PEO-PPO) block
polymers of the general structure A-B, (A-B).sub.n, A-B-A (e.g.,
Pluronic.RTM.), or (A-B-A).sub.n with A being the PEO part and B
being the PPO part and n being greater than 1. In another preferred
embodiment, the polymers used are branched polymers of
polyoxyethylene-polyoxypropylene (PEO-PPO) like tetra-functional
poloxamines (e.g., Tetronic.RTM.).
Methods of the Invention
[0065] The present invention provides an approach to the treatment
of lithiasis. In one embodiment a polymer is injected between the
inlet of a lumen and a calculi in said lumen to form a polymer plug
which occludes the lumen; the subsequent action of peristalsis
causes the polymer plug to traverse the lumen, forcing the calculi
out of the lumen.
[0066] One aspect of the present invention relates to a method of
treating lithiasis, comprising the steps of:
[0067] injecting into a lumen of a mammal at a first position
upstream from a calculi a first composition, wherein said first
composition does not contact said calculi; optionally injecting
into said lumen at a second position upstream from said calculi a
second composition, wherein said second composition does not
contact said calculi; thereby forming a polymer plug; and
[0068] allowing peristalsis to cause said polymer plug to traverse
said lumen, thereby forcing said calculi from said lumen.
[0069] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition is injected
into said lumen.
[0070] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is between about
1 cm and about 5 cm upstream of said calculi.
[0071] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is between about
2 cm and about 4 cm upstream of said calculi.
[0072] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is about 3 cm
upstream of said calculi.
[0073] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 3 mm.
[0074] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 1 mm.
[0075] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 0.5 mm.
[0076] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 0.1 mm
[0077] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition is injected
into said lumen through a percutaneous access device.
[0078] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition is injected
into said lumen through a catheter or a syringe.
[0079] In certain embodiments, the present invention relates to the
aforementioned method, wherein the catheter is a dual lumen
catheter or a triple lumen catheter.
[0080] In certain embodiments, the present invention relates to the
aforementioned method, wherein said lumen is or is a portion of a
kidney, gall bladder, ureter, urinary bladder, pancreas, salivary
gland, small intestine or large intestine.
[0081] In certain embodiments, the present invention relates to the
aforementioned method, wherein said lumen is or is a portion of a
ureter or kidney.
[0082] In certain embodiments, the present invention relates to the
aforementioned method, wherein said calculi is a kidney stone,
pancreatic stone, salivary stone, or biliary stone.
[0083] In certain embodiments, the present invention relates to the
aforementioned method, wherein said calculi is a kidney stone.
[0084] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammal is a human.
[0085] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition comprises a
contrast-enhancing agent.
[0086] 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. \
[0087] Another aspect of the present invention relates to a method
of treating lithiasis, comprising the steps of:
[0088] injecting into a lumen of a mammal at a first distance
upstream from a calculi a first composition comprising an inverse
thermosensitive polymer, wherein said first composition does not
contact said calculi; thereby forming a polymer plug;
[0089] optionally injecting into said lumen at a second distance
upstream from said calculi a second composition, wherein said
second composition does not contact said calculi; and
[0090] allowing peristalsis to cause said polymer plug to traverse
said lumen, thereby forcing said calculi from said lumen.
[0091] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition is injected
into said lumen.
[0092] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition is injected
into said lumen.
[0093] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is between about
1 cm and about 5 cm upstream of said calculi.
[0094] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is between about
2 cm and about 4 cm upstream of said calculi.
[0095] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is about 3 cm
upstream of said calculi.
[0096] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 3 mm
[0097] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 1 mm.
[0098] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 0.5 mm.
[0099] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 0.1 mm
[0100] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition is injected
into said lumen through a percutaneous access device.
[0101] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition is injected
into said lumen through a catheter or a syringe.
[0102] In certain embodiments, the present invention relates to the
aforementioned method, wherein the catheter is a dual lumen
catheter or a triple lumen catheter.
[0103] In certain embodiments, the present invention relates to the
aforementioned method, wherein said lumen is or is a portion of a
kidney, gall bladder, ureter, urinary bladder, pancreas, salivary
gland, small intestine or large intestine.
[0104] In certain embodiments, the present invention relates to the
aforementioned method, wherein said lumen is or is a portion of a
ureter or kidney.
[0105] In certain embodiments, the present invention relates to the
aforementioned method, wherein said calculi is a kidney stone,
pancreatic stone, salivary stone, or biliary stone.
[0106] In certain embodiments, the present invention relates to the
aforementioned method, wherein said calculi is a kidney stone.
[0107] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammal is a human.
[0108] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition comprises a
contrast-enhancing agent.
[0109] 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.
[0110] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is a block copolymer, random copolymer, graft polymer, or branched
copolymer.
[0111] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is a block polymer or a branched copolymer.
[0112] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is an optionally purified poloxamer or poloxamine.
[0113] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is optionally purified and selected from the group consisting of
poloxamine 1107, poloxamine 1307, poloxamer 338 and poloxamer
407.
[0114] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is an optionally purified poloxamer 407.
[0115] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition has a
transition temperature of between about 10.degree. C. and
40.degree. C.
[0116] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition has a
transition temperature of between about 15.degree. C. and
30.degree. C.
[0117] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition has a
transition temperature of about 25.degree. C.
[0118] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises
about 5% to about 30% of said inverse thermosensitive polymer.
[0119] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises
about 10% to about 25% said inverse thermosensitive polymer.
[0120] In certain embodiments, the present invention relates to the
aforementioned method, wherein the inverse thermosensitive polymer
has a polydispersity index from about 1.5 to 1.0.
[0121] In certain embodiments, the present invention relates to the
aforementioned method, wherein the inverse thermosensitive polymer
has a polydispersity index from about 1.2 to 1.0.
[0122] In certain embodiments, the present invention relates to the
aforementioned method, wherein the inverse thermosensitive polymer
has a polydispersity index from about 1.1 to 1.0.
[0123] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is an optionally purified poloxamer or poloxamine; and said first
composition has a transition temperature of between about
10.degree. C. and 40.degree. C.
[0124] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is an optionally purified poloxamer or poloxamine; and said first
composition has a transition temperature of between about
15.degree. C. and 30.degree. C.
[0125] In certain embodiments, the present invention relates to the
aforementioned method, wherein said inverse thermosensitive polymer
is an optionally purified poloxamer or poloxamine; and said first
composition has a transition temperature of about 25.degree. C.
[0126] Another aspect of the present invention relates to a method
of treating lithiasis, comprising the steps of:
[0127] injecting into a lumen of a mammal at a first distance
upstream from a calculi a first composition, wherein said first
composition does not contact said calculi;
[0128] injecting into said lumen at a second distance upstream from
said calculi a second composition, wherein said second composition
does not contact said calculi;
[0129] wherein said first composition and said second composition
admix, thereby forming a polymer plug;
[0130] optionally injecting into said lumen at a third distance
upstream from said calculi a third composition, wherein said third
composition does not contact said calculi; and
[0131] allowing peristalsis to cause said polymer plug to traverse
said lumen, thereby forcing said calculi from said lumen.
[0132] In certain embodiments, the present invention relates to the
aforementioned method, wherein said third composition is injected
into said lumen. In certain embodiments, the present invention
relates to the aforementioned method, wherein said third
composition is injected into said lumen.
[0133] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition is injected
into said lumen.
[0134] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is between about
1 cm and about 5 cm upstream of said calculi.
[0135] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is between about
2 cm and about 4 cm upstream of said calculi.
[0136] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first position is about 3 cm
upstream of said calculi.
[0137] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 3 mm.
[0138] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 1 mm.
[0139] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 0.5 mm.
[0140] In certain embodiments, the present invention relates to the
aforementioned method, wherein the distance between said first
position and said second position is less than about 0.1 mm.
[0141] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first and second compositions
are injected into said lumen through a percutaneous access
device.
[0142] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first and second compositions
are injected into said lumen through a catheter or a syringe.
[0143] In certain embodiments, the present invention relates to the
aforementioned method, wherein the catheter is a dual lumen
catheter or a triple lumen catheter.
[0144] In certain embodiments, the present invention relates to the
aforementioned method, wherein said lumen is or is a portion of a
kidney, gall bladder, ureter, urinary bladder, pancreas, salivary
gland, small intestine or large intestine.
[0145] In certain embodiments, the present invention relates to the
aforementioned method, wherein said lumen is or is a portion of a
ureter or kidney.
[0146] In certain embodiments, the present invention relates to the
aforementioned method, wherein said calculi is a kidney stone,
pancreatic stone, salivary stone, or biliary stone.
[0147] In certain embodiments, the present invention relates to the
aforementioned method, wherein said calculi is a kidney stone.
[0148] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammal is a human.
[0149] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition comprises a
contrast-enhancing agent.
[0150] 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.
[0151] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises an
anionic, cationic, or non-ionically crosslinkable polymer.
[0152] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition 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.
[0153] In certain embodiments, the present invention relates to the
aforementioned method, wherein said second composition comprises
phosphate, citrate, borate, succinate, maleate, adipate, oxalate,
calcium, magnesium, barium, strontium, or a combination
thereof.
[0154] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises a
polymer selected from the group consisting of alginic acid, sodium
alginate, potassium alginate, sodium gellan and potassium gellan;
and said second composition comprises calcium, magnesium or
barium.
[0155] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises a
polymer selected from the group consisting of alginic acid, sodium
alginate or potassium alginate; and said second composition
comprises calcium.
[0156] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises a
polymer selected from the group consisting of sodium gellan and
potassium gellan; and said second composition comprises
magnesium.
[0157] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises
hyaluronic acid; and said second composition comprises calcium.
[0158] In certain embodiments, the present invention relates to the
aforementioned method, wherein said first composition comprises
polyvinyl alcohol; and said second composition comprises
borate.
[0159] In one embodiment the polymer solution can be introduced
through a catheter. The catheter may be a dilatation catheter. In
one embodiment, the catheter is 3-10 French in size, and more
preferably 3-6 French. In another embodiment, a catheter can be
used to dispense one or more fluids other than, or in addition to,
the polymer solution. In said embodiment the catheter may be a
multiple lumen catheter with one lumen for the delivery of the
polymer solution, other lumen for the delivery of other fluids such
as a contrast agent solution.
[0160] In another embodiment, the syringe or other mechanism may be
used to inject the polymer solution into the body can be, for
example, a 1-100 cc syringe, a 1-50 cc syringe or a 1-5 cc.
Pressure applied to the syringe can be applied by hand or by an
automated syringe pusher.
EXEMPLIFICATION
[0161] 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
Gelation Temperature of Selected Pluronic.RTM. and Tetronic.RTM.
Polymer Solutions
[0162] The 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.
TABLE-US-00001 TABLE 1 polymer concentration temperature Tetronic
1107 25 w % 27.degree. C. Tetronic 1107 20 w % 34.degree. C.
Purified Tetronic 1107 25 w % 22.degree. C. Purified Tetronic 1107
20 w % 32.5.degree. C. Tetronic 1307 25 w % 24.5.degree. C.
Tetronic 1307 20 w % 31.degree. C. Purified Tetronic 1307 25 w %
20.degree. C. Purified Tetronic 1307 20 w % 26.degree. C. Pluronic
F108 25 w % 26.degree. C. Pluronic F108 20 w % 60.degree. C.
Purified Pluronic F108 25 w % 19.degree. C. Purified Pluronic F108
20 w % 26.degree. C.
Example 2
Gelation Temperature of Selected Pluronic.RTM. and Tetronic.RTM.
Polymer Solutions with Iodinated Contrast Agent
[0163] Purified polymers were weighed into 50 mL centrifuge tubes
and a 1:1 mixture of saline and 100% Omnipaque 300 were added until
a specific weight percentage was reached. Gelation points were
measured in a Brookfield viscometer and the point at which the
viscosity exceeded the range of the plate/cone (greater than about
102,000 cP) was called the gelation point. All solutions were
further heated to 37.degree. C. to ascertain that the material
still exceeded the viscosity range and remained a gel. All gels
passed.
TABLE-US-00002 TABLE 2 polymer concentration temperature Purified
Tetronic 1107 20 w % 24.degree. C. Purified Tetronic 1307 21 w %
26.5.degree. C. Purified Pluronic F108 18 w % 21.5.degree. C.
Purified Pluronic F127 18 w % 18.degree. C.
Example 3
Dissolution Time Under Static Conditions in Saline
[0164] The dissolution of the purified poloxamer 407 gel was tested
by injecting 0.5 milliliter of the gel into a petri dish covered in
saline at 37.degree. C. The gel was visualized by small addition of
methylene blue and the dissolution of the gel was followed
visually. Two different shapes of the gels were used for the
dissolution tests: a sphere which has the least amount of surface
area; and a string, which has the highest surface area, in which a
20 gauge syringe was used to extrude the string of polymer onto the
bottom of the Petri dish.
[0165] The petri dish was not disturbed and every minute, the petri
dish was observed visually and complete dissolution was confirmed
by swirling the petri dish.
[0166] The dissolution was dependent on the concentration of the
polymer. The lower the polymer concentration, the faster the gel
dissolved as depicted in the FIG. 5. Further, the dissolution was
dependent on the surface area in direct contact with the
surrounding liquid, the sphere-shaped gel taking longer to dissolve
than the string.
[0167] These in-vitro experiments probably still overestimate the
real dissolution times as there was no pulsatile force on the gel,
which would probably speed up the dissolution.
Example 4
Dissolution Time Under Static Conditions in Urine
[0168] The dissolution of the 22.5% purified poloxamer 407 gel was
tested by injecting 2.5 milliliter of the gel into a petri dish
covered in about 100 mL urine at 37.degree. C. A syringe without a
needle was used to extrude a string of polymer onto the bottom of
the Petri dish. The gel was visualized by small addition of
methylene blue and the dissolution of the gel was followed
visually. Upon extrusion the string broke in two. The petri dish
was not disturbed and every minute, the petri dish was observed
visually and complete dissolution was confirmed by swirling the
petri dish. The complete dissolution time (about 26 minutes) was
identical for the two strings.
Example 5
Pig Ureter In-Vivo Experiments
[0169] A 22.5 w % solution of purified Poloxamer PF127, colored
with methylene blue, in a Medallion 5 ml syringe was used. In each
of the three pigs, an artificial stone, made of plaster of Paris,
was surgically implanted in the right ureter a few centimeters
above the site of the incision. The solution was then injected
behind the stone through the same incision site, using a 3F
catheter [Embocath HIC 100 from BioSphere Medical, lot#03W-6930].
Immediately prior to the injection the catheter was flushed with 10
cc of cold saline to keep it cool during the injection and avoid
hardening of the polymer within the catheter. Each procedure was
monitored with a camera inserted in the ureter between the stone
and the incision site.
[0170] Pig #1--3 ml of solution were injected behind the stone that
occluded ca. 1/4 to 1/3 of the cross-section of the ureter, and
created a well visible blue polymer plug that completed occluded
the ureter behind the stone. After a little over 1 minute, the
polymer plug or some urine accumulating behind it created
contraction waves of the ureteral walls (peristalsis) which forced
the plug to slide forward towards the camera and out of the ureter,
carrying with it the entire stone, without any need for
lithotripsy.
[0171] Pig #2--Same as the 1.sup.st pig but the stone was slightly
larger, and immediately after the injection of the polymer
lithotripsy (EHL) was used to break the stone into small fragments.
Within one minute of the completion of lithotripsy peristalsis
started and the stone debris were pushed by the sliding plug out of
the ureter.
[0172] Pig #3--Same as the 2.sup.nd pig but the stone was even
larger. Within one minute of the completion of lithotripsy
peristalsis started and the stone debris were pushed by the sliding
plug out of the ureter.
INCORPORATION BY REFERENCE
[0173] All of the U.S. patents and U.S patent application
publications cited herein are hereby incorporated by reference.
EQUIVALENTS
[0174] 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.
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