U.S. patent application number 13/914664 was filed with the patent office on 2013-10-24 for cannula system.
The applicant listed for this patent is Covidien LP. Invention is credited to Ferass Abuzaina, Ahmad Robert Hadba.
Application Number | 20130281976 13/914664 |
Document ID | / |
Family ID | 39847051 |
Filed Date | 2013-10-24 |
United States Patent
Application |
20130281976 |
Kind Code |
A1 |
Abuzaina; Ferass ; et
al. |
October 24, 2013 |
CANNULA SYSTEM
Abstract
The present disclosure provides a cannula useful for introducing
a thermally responsive polymer in situ. In embodiments, the cannula
possesses more than one cannula, with the thermally responsive
polymer introduced in one cannula, and a material such as a coolant
in a second cannula which prevents premature gelling of the
thermally responsive polymer.
Inventors: |
Abuzaina; Ferass; (Shelton,
CT) ; Hadba; Ahmad Robert; (Fort Worth, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Covidien LP |
Mansfield |
MA |
US |
|
|
Family ID: |
39847051 |
Appl. No.: |
13/914664 |
Filed: |
June 11, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12147046 |
Jun 26, 2008 |
8480651 |
|
|
13914664 |
|
|
|
|
60963049 |
Aug 2, 2007 |
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Current U.S.
Class: |
604/506 |
Current CPC
Class: |
A61M 2025/0039 20130101;
A61B 2017/00495 20130101; A61M 25/0026 20130101; A61B 17/00491
20130101 |
Class at
Publication: |
604/506 |
International
Class: |
A61M 25/00 20060101
A61M025/00 |
Claims
1-14. (canceled)
15. A method of applying a composition comprising: obtaining a
composition comprising a thermally responsive polymer, wherein the
composition is in a low viscosity state at a pre-treatment
temperature prior to being injected into a polyp and a higher
viscosity state at a treatment temperature that is higher than the
pre-treatment temperature; administering the composition to the
polyp using a multi-lumen cannula comprising: a proximal end and a
distal end; at least one lumen configured to permit the passage of
a coolant; and at least a second lumen configured to permit the
passage of the composition comprising the thermally responsive
polymer; warming the composition thereby increasing the
composition's viscosity to the higher viscosity state, and removing
the polyp while the composition comprising the thermally responsive
polymer remains substantially inside the polyp.
16. The method of claim 15, wherein the cannula comprises a coaxial
double lumen cannula comprising an inner lumen possessing the
composition comprising the thermally responsive polymer and an
outer lumen possessing the coolant.
17. The method of claim 16, wherein the distal end of the outer
lumen of the cannula possesses a device selected from the group
consisting of valves, stoppers and seals, to prevent the coolant
from exiting the distal end of the cannula.
18. The method of claim 16, wherein the distal end of the inner
lumen of the cannula possesses a dispensing needle.
19. The method of claim 15, wherein the coolant is selected from
the group consisting of water, saline, air, nitrogen, argon,
helium, carbon dioxide, ethanol, and combinations thereof.
20. The method of claim 15, wherein the coolant comprises a
solution selected from the group consisting of ammonium nitrate
crystals in water, potassium iodide in water, ammonium chloride in
water, ammonium acetate in water, potassium thiocyanate in water,
ammonium thiocyanate in water, sodium thiosulfate in water,
ammonium bromide in water, urea based solutions, and combinations
thereof.
21. The method of claim 15, wherein the composition comprising the
thermally responsive polymer is selected from the group consisting
of alkyl cellulose, hydroxyalkyl cellulose, cellulosic ethers,
poloxamers, polyoxyalkylene block copolymers,
poly(n-isopropylacrylamide), PEG triblock copolymers of L-lactide,
glycolide, polyglycolide, copolymers of glycolide,
glycolide/lactide copolymers, glycolide/trimethylene carbonate
copolymers, D, L-lactide, L-polylactides, poly-L-lactide,
poly-DL-lactide copolymers, L-lactide/DL-lactide copolymers,
.epsilon.-caprolactone, trimethylene carbonate, PEG-grafted
chitosan, pectin-chitosan mixtures, methyl cellulose, gelatin,
thermoreversible polymers, and combinations thereof.
22. The method of claim 15, wherein the composition comprising the
thermally responsive polymer comprises a solvent and from about 10%
to about 50% by weight of one or more thermally responsive
viscosity modifiers comprising a mixture of a first block copolymer
of ethylene oxide and propylene oxide and a second block copolymer
of ethylene oxide and propylene oxide.
23. The method of claim 22, wherein the composition comprising the
thermally responsive polymer comprises a first block copolymer
having an average molecular weight of from about 7680 to about
14600 present in an amount of about 10% to about 50% by weight of
the total composition, in combination with a second block copolymer
having an average molecular weight of from about 7680 to about
14600 present in an amount of from about 5% to about 50% by weight
of the total composition.
24. The method of claim 15, wherein the composition comprising the
thermally responsive polymer further comprises one or more active
ingredients selected from the group consisting of enzymes,
vasoconstrictors, chemotherapeutic agents, antimicrobials,
antibiotics, and combinations thereof.
25. The method of claim 15, wherein the composition comprising the
thermally responsive polymer has a viscosity of from about 50
centipoise to about 200,000 centipoise at about 25.degree. C.
26. The method of claim 15, wherein the composition comprising the
thermally responsive polymer is a liquid at a pre-treatment
temperature of about 25.degree. C. and a gel at a treatment
temperature of about 37.degree. C.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to U.S.
Provisional Patent Application No. 60/963,049, filed Aug. 2, 2007,
the entire disclosure of which is incorporated by reference
herein.
TECHNICAL FIELD
[0002] The present disclosure relates to cannulas suitable for
introducing thermoreversible polymeric materials in situ.
BACKGROUND OF RELATED ART
[0003] A polyp is generally a growth that projects from a membrane
in the body. The shape of a polyp is often described as
pedunculated or sessile. Pedunculated polyps grow on stalks, while
sessile polyps may have broad bases and a flat appearance. Often,
polyps form on mucous membranes such as those lining the colon,
bladder, uterus, cervix, vocal cords, and/or nasal passage and
protrude into a body cavity. Polyps are problematic in that they
may block a passage, and/or may become cancerous. Generally, the
larger the polyp, the more likely it is to become cancerous.
[0004] Endoscopic polypectomy procedures are effective in removing
pedunculated polyps; however, sessile polyps are often problematic.
For example, because of their flat, diffuse appearance, sessile
polyps may be difficult to snare and excise with electrocautery. To
facilitate excision of some polyps, saline may be injected into the
submucosa of a polyp to create an artificial cushion that raises
the polyp. However, saline has a short residence time in the
submucosa: it usually clears within 4 to 5 minutes after
injection.
[0005] In addition, large polyps are often difficult to remove as a
whole, so they are often excised in piecemeal fashion. After the
first excision of polyp tissue, injected solution may escape from
the submucosa causing the polyp to collapse, thus making it
difficult to remove the remaining portions of the polyp. Although
saline may be re-injected, it escapes quickly and is not very
effective in raising the remaining portions of the polyp.
[0006] Attempts to improve submucosa residence time of injection
solutions have been reported. For example, solutions of glycerin,
dextrose, hyaluronic acid, and hydroxpropyl cellulose have been
reported as injection solutions. In some cases, hyaluronic acid may
be effective. The average residence time of hyaluronic acid
solutions in porcine esophagus is reportedly 21.5 minutes. However,
these solutions may still leak out of the submucosal layer once the
cushion is breached during the endoscopic dissection or
polypectomy.
[0007] Means for introducing injection solutions into a polyp
include endoscopic methods which may, in embodiments, include the
use of catheters and/or cannulas. As is within the purview of those
skilled in the art, cannulas may include tubular, flexible,
surgical instruments for withdrawing fluids from (or introducing
fluids into) a cavity of the body. Cannulas may have a single lumen
or may have multiple lumens; multi-lumen cannulas, including dual
lumen cannulas, are also within the purview of those skilled in the
art.
[0008] Various configurations multi-lumen catheters and/or cannulas
are also known. For example, U.S. Pat. No. 4,385,631 discloses a
hemodialysis catheter having two circular lumens arranged side by
side. U.S. Pat. No. 4,099,528 discloses a coaxial double lumen
cannula and U.S. Pat. No. 4,493,696 describes a coaxial double
lumen catheter.
[0009] There remains room for improvement in compositions and
methods for performing endoscopic polypectomy procedures, as well
as instruments suitable for introducing polymeric materials into
the body.
SUMMARY
[0010] The present disclosure provides multi-lumen cannulas
suitable for introducing thermally responsive polymers in situ.
Such multi-lumen cannulas may include, in embodiments, a proximal
end and a distal end, at least one lumen configured to permit the
passage of a coolant, and at least one additional lumen configured
to permit the passage of a composition including a thermally
responsive polymer, wherein the thermally responsive polymer is in
a low viscosity state at a pre-treatment temperature and a higher
viscosity state at a treatment temperature that is higher than the
pre-treatment temperature.
[0011] In embodiments, cannulas of the present disclosure may be
utilized to introduce thermally responsive polymers into polyps to
aid in their removal.
[0012] Methods for applying compositions with these devices are
also provided. In embodiments, methods of the present disclosure
may include obtaining a composition including a thermally
responsive polymer, wherein the composition is in a low viscosity
state at a pre-treatment temperature prior to being injected into a
polyp and a higher viscosity state at a treatment temperature that
is higher than the pre-treatment temperature. The compositions may
be administered to the polyp using a multi-lumen cannula including
a proximal end and a distal end, at least one lumen configured to
permit the passage of a coolant, and at least a second lumen
configured to permit the passage of the composition including the
thermally responsive polymer. The composition may be warmed thereby
increasing the composition's viscosity to the higher viscosity
state, and the polyp may be removed while the composition including
the thermally responsive polymer remains substantially inside the
polyp.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Various embodiments of the present disclosure will be
described herein below with reference to the figures wherein:
[0014] FIG. 1 is a cross section of a cannula of the present
disclosure having an inner lumen capable of carrying a thermally
responsive polymer and an outer lumen capable of carrying a
coolant;
[0015] FIG. 2 is a depiction of a cannula of the present disclosure
possessing a needle therein;
[0016] FIG. 3 is another depiction of a cannula of the present
disclosure possessing a needle therein with the proximal end of the
cannula attached to a double-lumen syringe; and
[0017] FIG. 4 is another depiction of a cannula of the present
disclosure possessing a needle therein, a double-lumen syringe
attached to the proximal end of the cannula, and a valve, stopper
or seal at the distal end of the cannula.
DETAILED DESCRIPTION
[0018] The present disclosure provides cannulas suitable for
introducing compositions containing one or more thermally
responsive polymers into the body. In embodiments, the compositions
may be in a low viscosity state such as a liquid at a pre-treatment
temperature, and a higher viscosity state such as a gel at a
treatment temperature that is higher than the pre-treatment
temperature.
[0019] In accordance with the present disclosure, a multi-lumen
cannula may be utilized to introduce the composition containing one
or more thermally responsive polymers into the body. The
composition containing one or more thermally responsive polymers
may be introduced into the body through at least one lumen, with at
least one other lumen of the multi-lumen cannula containing a
coolant which prevents premature gelling of the thermally
responsive polymer as it is introduced into the body or at any
injection site.
[0020] A multi-lumen cannula for use in accordance with the present
disclosure should possess at least two lumens. In embodiments, as
noted above, at least one lumen may contain a coolant, with at
least one other, lumen possessing the thermally responsive polymer
composition. In other embodiments, the cannula may possess
additional lumens which may house and permit the transit of other
suitable items and/or devices including, but not limited to, one or
more medicines, drugs, blood, medical devices, guide wires, snares
suitable for use in polypectomy procedures, needles, optical
fibers, fiber optic imaging devices, fiber optic diagnostic probes,
combinations thereof, and the like.
[0021] In embodiments, a suitable multi-lumen cannula may be a
double lumen cannula. A double lumen cannula may possess any
configuration within the purview of those skilled in the art. For
example, in some embodiments, a single tube with a horizontal
division of the tube which places the lumens of the cannula in
immediate juxtaposition may be utilized.
[0022] In other embodiments, a coaxial double lumen cannula may be
utilized to introduce the composition containing one or more
thermally responsive polymers into the body. Such a cannula may
possess concentric lumens, disposed one within the other. A
cross-section of such a cannula, which should be apparent to one
skilled in the art, is depicted in FIG. 1. As depicted in FIG. 1,
cannula 10 may include two lumens, inner cannula lumen 12 and outer
cannula lumen 14. Inner wall 16 may encompass inner lumen 12, while
outer wall 18 may encompass outer lumen 14. The diameter of the
inner lumen may be from about 1 mm to about 2 mm, in embodiments
from about 1.25 mm to about 1.75 mm. The diameter of cannula 10 may
be less than about 2.8 mm, in embodiments from about 2.2 mm to
about 2.8 mm.
[0023] The composition containing one or more thermally responsive
polymers may be introduced into the body via the inner lumen or the
outer lumen; the other lumen may contain a coolant to prevent
premature gelling of the thermally responsive polymer. For example,
the composition containing one or more thermally responsive
polymers may be introduced into the body via the outer lumen with
the coolant contained in the inner lumen. In other embodiments, the
composition containing one or more thermally responsive polymers
may be introduced into the body via the inner lumen, with the
coolant being present in the outer lumen of the cannula.
[0024] A cannula in accordance with the present disclosure may be
of any suitable length; in embodiments from about 1 meter to about
meters long, in other embodiments from about 1.25 meters to about
2.3 meters long.
[0025] The cannulas of the present disclosure may be utilized to
deliver thermally responsive polymers endoscopically through a
conventional colonoscope. Accordingly, while a cannula of the
present disclosure may be constructed of any material within the
purview of those skilled in the art, in embodiments a cannula of
the present disclosure may be constructed of a comparatively soft
medical grade plastic or metals such as stainless steel, titanium,
and the like. Specific synthetic materials which may be utilized
include, but are not limited to, fluoropolymers including
polytetrafluoroethylene, polyurethane, polyethylene, polypropylene,
high density polyethylene, nylons, polyethylene terephthalate,
silicones, combinations thereof, and the like.
[0026] In embodiments, the inner lumen of the cannula may possess a
Luer lock fitting at one end and a short dispensing needle at the
other end, i.e., the distal end, having a length of from about 3 mm
to about 8 mm, in embodiments about 4 mm, with a gauge of from
about 14 gauge to about 23 gauge, in embodiments from about 18
gauge to about 21 gauge. An example of such a cannula is depicted
in FIG. 2. Cannula 10 may possess outer tube 18 surrounding outer
cannula lumen 14, inner tube 16 surrounding inner cannula lumen 12,
with needle 40 affixed to the distal end of inner tube 16 adjacent
distal end 20 of cannula 10. Outer tube 18 functions as a
protective sheath to protect the needle and provide a working
channel for any scope utilized therewith (not shown). The outer
diameter of outer tube 18 may be of a suitable size, in embodiments
less than or equal to about 2.7 mm. The diameter of the inner tube
16 is small enough to permit passage within outer tube 18. The
inner diameter of inner tube 16 may be, in embodiments, from about
1 mm to about 2 mm. Needle 40 may, in embodiments, be from about 14
gauge to about 23 gauge, and may be of a length of from about 3 mm
to about 8 mm. A thermally responsive polymer may be introduced
into inner tube 16 at its proximal end 50 adjacent proximal end 30
of cannula 10 utilizing a luer lock syringe, a mechanically
advancing gun, or similar device (not shown).
[0027] In embodiments, the distal end of the outer lumen of the
cannula may be open. Where a coolant is present in the outer lumen
of the cannula, a separate port with a luer lock fitting may be
utilized to inject the coolant into the outer lumen or the same
port may be utilized to simultaneously inject both the thermally
responsive polymer and the coolant. Where the same port is utilized
to simultaneously inject both the thermally responsive polymer and
the coolant, a double-lumen syringe may be utilized with one
compartment containing the polymer solution for introduction into
the inner lumen and a second compartment containing the coolant for
introduction into the outer lumen. An example of such a cannula is
depicted in FIG. 3. As set forth in FIG. 3, cannula 10, possessing
outer tube 18, inner tube 16, and needle 40 at the distal end of
inner tube 16 within distal end 20 of cannula 10, may have a closed
proximal end 60 and access ports 70 and 75 which may be connected
to a double-lumen syringe 80, possessing lumens 85 and 90. Lumen 85
may possess a thermally responsive polymer which may be introduced
via access port 70 into inner cannula lumen 12, while lumen 90 may
possess a coolant which may be introduced via access port 75 into
outer cannula lumen 14. Double lumen syringe 80 may possess backing
100 on plungers 110 and 120 to facilitate the simultaneous
introduction of the thermally responsive polymer and the coolant.
In either case, the polymeric material may be introduced into the
body via the inner lumen which may, in embodiments, have a needle
40 as described above attached thereto; the coolant may be
dispensed out of the distal end of the cannula into the body, for
example the colon, where the cannula is utilized to introduce the
thermally responsive polymer into a polyp during a polypectomy.
[0028] In yet other embodiments, the distal end of the outer lumen
of the cannula may be closed so that the coolant is not discharged
into the body. In this embodiment, a valve, stopper, seal, or
similar device may be placed at the distal end of the outer lumen
which prevents the coolant from exiting the distal end of the
cannula. An example of such a cannula is depicted in FIG. 4. As set
forth in FIG. 4, cannula 10, possessing outer tube 18, inner tube
16, and needle 40 at the distal end of inner tube 16 within distal
end 20 of cannula 10, may have a closed proximal end 60 and access
ports 70 and 75 which may be connected to a double-lumen syringe
80, possessing lumens 85 and 90. Lumen 85 may possess a thermally
responsive polymer which may be introduced via access port 70 into
inner cannula lumen 12, while lumen 90 may possess a coolant which
may be introduced via access port 75 into outer cannula lumen 14.
Double lumen syringe 80 may possess backing 100 on plungers 110 and
120 to facilitate the simultaneous introduction of the thermally
responsive polymer and the coolant. Cannula 10 may possess a
stopper, valve, or seal 130 at its distal end 20 which permits
passage of needle 40 therethrough but prevents any coolant from
exiting outer cannula lumen 14. In embodiments, it may be desirable
to determine the volume of the outer lumen and introduce that
amount of coolant therein, to minimize backflow of the coolant from
the proximal end of the cannula during a surgical procedure.
[0029] Any coolant capable of preventing premature gelling of the
thermally responsive polymer may be utilized. Suitable coolants
which may be included in one of the lumens, in embodiments the
outer lumen, include, for example, cooled liquids such as water,
saline, ethanol, combinations thereof, and the like, and/or cooled
gases such as air, nitrogen, argon, helium, carbon dioxide,
combinations thereof, and the like. In some cases, gases may be
cooled to a liquid state, for example, liquid nitrogen.
[0030] In other embodiments, suitable coolants may include
solutions such as ammonium nitrate crystals in water, which are
capable of dissolving in water while absorbing heat and cooling
their surroundings in a few seconds. Similar solutions which may be
utilized as the coolant include, but are not limited to, potassium
iodide in water, ammonium chloride in water, ammonium acetate in
water, potassium thiocyanate in water, ammonium thiocyanate in
water, sodium thiosulfate in water, ammonium bromide in water,
combinations thereof, and the like. Other solutions which may be
utilized as a coolant include urea based solutions commercially
available as INSTAKOOL.TM. from Nortech Laboratories, Inc.
(Farmingdale, N.Y.), and the like. In addition, combinations of
chemicals known to produce endothermic reactions, for example,
baking soda with citric acid, and the like, may be combined and
utilized as a coolant.
[0031] Combinations of the above-identified coolants may also be
utilized in some embodiments.
[0032] In embodiments, the above coolants may be utilized without
any external temperature control. In other embodiments, the
temperature of the coolant may be adjusted utilizing external
means, for example, a suitable control system such as a Peltier
cooler, a Joule-Thompson cryostat, a Stirling engine, an
independent closed-loop refrigeration system, and the like. Such
temperature control systems and their operation are within the
preview of those skilled in the art.
[0033] Thermally responsive polymers which may be utilized with the
cannula of the present disclosure may include one or more polymeric
substances that undergo a change in viscosity with a change in
temperature, for example, warming. In embodiments, the thermally
responsive polymers may be in a solution including at least one
solvent, with other excipients and/or ingredients to form a
composition of the present disclosure. In embodiments, additional
excipients and/or ingredients may be added to facilitate usage of
the compositions and adjust their viscosity, for example, during a
polypectomy procedure. As used herein, "viscosity" refers to a
measure of the resistance of a fluid to deform under shear stress
and is used herein to describe a fluid's internal resistance to
flow. For example, water has a relatively lower viscosity, while
substances like vegetable oil or honey have a higher viscosity.
[0034] Compositions utilized in accordance with the present
disclosure may include a pharmaceutically acceptable carrier or
diluent, vehicle or medium, for example, a carrier, vehicle or
medium that is compatible with the tissues to which they will be
applied. The term "dermatologically or pharmaceutically
acceptable," as used herein, means that the compositions or
constituents thereof are suitable for use in contact with tissues
or for use in patients in general without undue toxicity,
incompatibility, instability, allergic response, and the like.
[0035] The present active ingredients and formulations containing
them in accordance with the present disclosure can be injected into
the submucosa of a polyp in amounts sufficient to treat the
affected area. As used herein the word "treat," "treating" or
"treatment" refers to using the active ingredients and/or
compositions of the present disclosure prophylactically to prevent
outbreaks of any undesirable conditions, or therapeutically to
ameliorate an existing undesirable condition. A number of different
treatments are now possible, which reduce and/or eliminate
undesirable conditions.
[0036] As used herein "undesirable condition" refers to any
detectable tissue manifestations caused by a polyp or removal
thereof. Such manifestations can appear due to a number of factors
such as, for example, trauma and/or other diseased or dysfunctional
state. Non-limiting examples of such manifestations include the
development of bleeding, cancer, inflammation, flakiness and/or
other forms of tissue abnormality, and combinations thereof. It is
understood, that the listed undesirable conditions are non-limiting
and that only a portion of the conditions suitable for treatment in
accordance with the present disclosure are listed herein.
[0037] Suitable polymers for use as the thermally responsive
polymers in accordance with the present disclosure include, but are
not limited to, thermoreversible polymers, poloxamers,
polyoxyalkylene block copolymers, alkyl cellulose, hydroxyalkyl
cellulose, cellulosic ethers, poly(n-isopropylacrylamide), PEG
triblock copolymers of L-lactide, glycolide, polyglycolides (PGA),
copolymers of glycolides such as glycolide/lactide copolymers
(PGA/PLLA) and/or glycolide/trimethylene carbonate copolymers
(PGA/TMC), D, L-lactide, L-polylactides (PLA), stereocopolymers of
polylactides such as poly-L-lactide (PLLA), poly-DL-lactide
copolymers and L-lactide/DL-lactide copolymers,
.epsilon.-caprolactone, trimethylene carbonate (TMC), PEG-grafted
chitosan, pectin-chitosan mixtures, methyl cellulose, gelatin, and
combinations thereof. Other suitable polymers include glycerin,
dextrose, hyaluronic acid, hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxyl propyl methyl cellulose (HPMC), combinations
thereof, and the like.
[0038] The polymer may be dissolved in a solvent at a concentration
of from about 10% to about 70% by weight of the solution, in
embodiments from about 20% to about 60% by weight of the solution;
thus the solvent may be present in an amount from about 90% to
about 30% by weight of the solution, in embodiments from about 80%
to about 40% by weight of the solution. In embodiments, the polymer
concentration may be such that the composition in accordance with
the present disclosure is in a low viscosity state at a
pre-treatment temperature and a higher viscosity state at a
treatment temperature that is higher than the pre-treatment
temperature. The polymer concentration may also be such that the
composition in accordance with the present disclosure is in a
highly viscous shear thinning state at a pre-treatment temperature
and a higher viscosity state at a treatment temperature that is
higher than the pre-treatment temperature.
[0039] As used herein, "pre-treatment temperature" refers to the
temperature of the compositions in accordance with the present
disclosure prior to being applied in the body of a patient, for
example the submucosa of a polyp. The pre-treatment temperature may
be room temperature, for example from about 23.degree. C. to about
25.degree. C., or any temperature below the treatment temperature.
As used herein, "treatment temperature" refers generally to the
temperature of the compositions in accordance with the present
disclosure after being applied to the body, for example the
submucosa of a polyp. The treatment temperature may be the normal
body temperature for a human, for example about 37.degree. C., or
any temperature found within the body, including, for example, the
temperature of a polyp to be treated. While the healthy human body
can maintain a fairly consistent body temperature of about
37.degree. C., the temperature may vary by about .+-.2.degree. C.,
with factors that may affect treatment temperature including the
age of the individual, the time of day, or the part of the body in
which the temperature is being measured at, and the like.
[0040] In embodiments, polyoxyalkylene polymers, including those
commercially available under the tradename PLURONICS, may be
utilized as the thermally responsive polymer. These polymers are
commercially available from BASF Corporation. Such polymers are
closely related block copolymers classified as
polyoxypropylene-polyoxyethylene condensates that terminate in
primary hydroxyl groups, and may be formed by the condensation of
propylene oxide into a propylene glycol nucleus followed by the
condensation of ethylene oxide onto both ends of the
polyoxypropylene base. The polyoxyethylene hydrophilic groups on
the ends of the base pre-polymer may be controlled in length so
that they account for from about 10% to about 80% by weight of the
final polymer. The PLURONIC polymer series of products may be
represented empirically by the formula: HO(C.sub.2H.sub.4O).sub.a
(C.sub.3H.sub.6O).sub.b (C.sub.2H.sub.4O).sub.c H, where a and c
are statistically equal.
[0041] The thermally responsive polymer may include a mixture of
other polyoxyalkylene polymers and/or various PLURONIC polymers. In
some embodiments, a first block copolymer and a second block
copolymer may be utilized. For example, a first block copolymer of
ethylene oxide and propylene oxide, such as PLURONIC F-127, may be
mixed with a second block copolymer of ethylene oxide and propylene
oxide, such as PLURONIC F-68, in a solution. In some embodiments,
the first block copolymer may be present in amounts of from about
10% to about 50% by weight of the solution. The first block
copolymer such as PLURONIC-F-127 may have a solubility in water at
about 4.degree. C. of greater than about 10%. (As concentration
increases, the gelation temperature decreases.) In other
embodiments, the first block copolymer may be present in amounts of
from about 15% to about 30% by weight of the solution.
[0042] The second block copolymer, in embodiments F-68, may be
present in an amount of from about 5% to about 50% by weight of the
solution. The second block copolymer, such as, for example,
PLURONIC F-68, may have a solubility in water at about 4.degree. C.
of greater than about 10%. In embodiments, the second block
copolymer may be present in an amount of from about 5% to about 25%
by weight of the solution.
[0043] The first block copolymer, the second block copolymer, or
both, may have a molecular weight of from about 7680 to about
14600. In embodiments, the first block copolymer may have a
molecular weight of from about 7680 to about 9510, while the second
block copolymer may have a molecular weight of from about 9840 to
about 14600.
[0044] In some embodiments, suitable compositions of the present
disclosure may include a solvent, from about 10% to about 50% by
weight of a first block copolymer of ethylene oxide and propylene
oxide, and from about 5% to about 50% by weight of a second block
copolymer of ethylene oxide and propylene oxide. In other
embodiments, suitable compositions may include an aqueous solvent,
and about 15% to about 50% by weight of a thermally responsive
polymer admixture.
[0045] In embodiments, the first and second block copolymers may be
thermoreversible. Suitable thermoreversible polymers may be added
to the compositions in accordance with the present disclosure in an
amount sufficient to reversibly change the viscosity thereof in
response to changes in temperature. For example, a composition
having a high viscosity at 37.degree. C. may thin and have a low
viscosity at 25.degree. C., yet thicken again upon application of
heat. Thus, such a composition may be a liquid at about 25.degree.
C. and a gel at a treatment temperature of about 37.degree. C.
[0046] In embodiments, thermoreversible polymers may be added to an
aqueous solution incorporating a stable combination or admixture of
one or more thermoreversible polymers and/or thermally responsive
polymers in amounts sufficient to effectively produce reversible
gelation at predetermined temperatures. As used herein, reversible
gelation refers to the increase and/or decrease in the viscosity of
a composition due to a variation in temperature, where the
composition becomes a gel or gel-like at one temperature, and a
liquid at another lower temperature. Non-limiting examples of
suitable thermoreversible polymers for use herein include alkyl
celluloses, hydroxyalkyl celluloses, cellulosic ethers,
PLURONIC.RTM. polymers and TETRONIC.RTM. polymers, and combinations
thereof. In embodiments, thermoreversible polymers may be added in
an amount of from about 10% to about 50% by weight of the
composition of the present disclosure.
[0047] In embodiments, compositions for use with a cannula in
accordance with the present disclosure may include hyaluronic acid
and/or derivatives thereof, such as sodium hyaluronic acid. In
other embodiments, the compositions in accordance with the present
disclosure may be devoid of hyaluronic acid and/or derivatives
thereof such as sodium hyaluronic acid, or hyaluronic acid or
derivatives thereof combined with any other chemical.
[0048] In embodiments, compositions in accordance with the present
disclosure may transition from a liquid state to a gel or gel-like
state at a temperature of from about 5.degree. C. to about
40.degree. C., in embodiments at a temperature of from about
15.degree. C. to about 37.degree. C., and in other embodiments at a
temperature of from about 25.degree. C. to about 35.degree. C. In
embodiments, the transition temperature can be modified by
including polymers such as PLURONIC F-68 in the composition.
[0049] Additionally, additives may be utilized to adjust the
temperature at which the compositions of the present disclosure
form a semi-solid, sometimes referred to herein as a gel. Any
additive within the purview of those skilled in the art may be
utilized. The additives may be hydrophilic or hydrophobic. In
embodiments, suitable hydrophilic additives include polyalkylene
oxides such as polyethylene glycols (PEG) of varying molecular
weights such as PEG 8000, PEG 10000 and the like, n-sodium octyl
sulfate, n-sodium decyl sulfate, n-dodecyl sulfate, n-hexadecyl
sulfate, n-octadecyl sulfate, combinations thereof, and the like.
Suitable other additives include, but are not limited to, salts
such as NaCl, Na.sub.2SO.sub.4, CaCl.sub.2, dyes such as methylene
blue and isosulfan blue, antifoam agents, bioactive agents,
combinations thereof, and the like. For example, in some
embodiments SURFYNOL.RTM. MD-20, a non-silicone solvent-free liquid
defoamer from Air Products and Chemicals, Inc. (Allentown, Pa.),
may be added to adjust the gel temperature of a composition of the
present disclosure.
[0050] In yet other embodiments, surfactants may be added to
compositions of the present disclosure to adjust the gel
temperature. Suitable surfactants are within the purview of those
skilled in the art and include, for example, sorbitan esters,
polyolefin based surfactants, ethoxylates, combinations thereof,
and the like. In some embodiments, commercially available
surfactants such as TRITON.RTM. 100 and TRITON.RTM. 114 (nonionic
surfactants from Sigma-Aldrich); TWEEN surfactants, SPAN
surfactants, combinations thereof, and the like, may be utilized.
Suitable TWEEN and SPAN surfactants include, but are not limited
to, monolaureates (TWEEN 20, TWEEN 21, SPAN 20), monopalmitates
(TWEEN 40, SPAN 40), monostearates (TWEEN 60, TWEEN 61, SPAN 60),
tristearates (TWEEN 65, SPAN 65), monooleates (TWEEN 80, TWEEN 81,
SPAN 80), trioleates (TWEEN 85, SPAN 85), combinations thereof, and
the like.
[0051] Where utilized, the amount of such additives utilized to
adjust the gel temperature of a composition of the present
disclosure may vary from about 0.01% by weight to about 4% by
weight of the composition, in embodiments from about 0.1% by weight
to about 2.5% by weight of the composition, in embodiments from
about 1% by weight to about 2.25% by weight of the composition, in
other embodiments from about 1.5% by weight to about 2% by weight
of the composition.
[0052] By adjusting the concentration of the copolymers and any
additives, liquid to semi-solid transition temperatures between a
pre-treatment temperature and a treatment temperature can be
achieved. For example, the concentration of the thermally
responsive polymers and the use of additives can be adjusted to
provide compositions in accordance with the present disclosure that
are a liquid at a pre-treatment temperature, and a gel at treatment
temperature. In embodiments, the liquid-gel transition temperature
may be from about 5.degree. C. to about 65.degree. C. In some
embodiments, the constituents can be selected in predetermined
amounts to produce high viscosity, shear thinning, gel
compositions. Such high viscosity, shear thinning, compositions may
be suitable for injection in a high viscosity state such as a gel.
In embodiments, the compositions in accordance with the present
disclosure at 25.degree. C. have a viscosity of from about 50
centipoise to about 200,000 centipoise.
[0053] In shear thinning embodiments, compositions in accordance
with the present disclosure transition from a semi solid and/or gel
state to a more viscous semi-solid and/or gel state at a
temperature from about 5.degree. C. to about 50.degree. C., in
embodiments at a temperature from about 15.degree. C. to about
40.degree. C., and in some embodiments at a temperature from about
30.degree. C. to about 37.degree. C. As compositions of the present
disclosure may be used in the human body, in embodiments it may be
desirable for the composition of the present disclosure to gel at a
temperature close to human body temperature, which is about
37.degree. C.
[0054] In other embodiments, a solvent utilized to form
compositions for use in accordance with the present disclosure may
be water, saline, or any pharmaceutically acceptable solvent in
amounts sufficient to solubilize the ingredients of the
composition. For example, a non-limiting example of a suitable
solvent includes an aqueous solution such as saline, resuspension
buffer such as a phosphate buffered saline, or a buffer suitable
for injection into a patient. Non-limiting examples of solvents
and/or buffers suitable for injection into a patient include a
pharmaceutically acceptable carrier such as a solution that does
not cause allergic or other adverse reaction with the patient upon
injection. The solvent may be present in an amount of from about
30% to about 90% by weight of the total composition. In
embodiments, the concentration of water in the composition can be
from about 30% to about 90% by weight of the composition, and/or
from about 40% to about 80% by weight of the composition. The water
used in forming the aqueous solution may be purified, as by
distillation, filtration, ion-exchange, and the like.
[0055] Other excipients can be added to the compositions of the
present disclosure in amounts sufficient to promote the removal of
one or more polyps. For example, a dye may be added to the
compositions to help the surgeon see the polyp better during the
removal process. Non-limiting examples of suitable dyes include
methylene blue, isosulfan blue, and combinations thereof. Dyes may
be added in an amount of about 0.1% to about 2% by weight of the
total composition.
[0056] Active ingredients can be added to the compositions of the
present disclosure in amounts sufficient to benefit the patient and
the procedure for which the composition is provided, in embodiments
a polypectomy procedure. While the amount of active agent used will
depend on a number of factors including the specific active agent
chosen and the benefit to be achieved, generally, an amount of from
about 0.01% to about 10% by weight of the total composition may be
suitable. Non-limiting examples of suitable active ingredients
include enzymes such as thrombin that converts fibrinogen to
fibrin, vasoconstrictors such as epinephrine, norepinephrine,
angiotensin, or vasopressin, chemotherapeutic agents such as
fluorouracil (5-FU), antimicrobials, antibiotics, and combinations
of these active agents.
[0057] In embodiments, compositions and product forms for use in
accordance with the present disclosure contain one or more active
ingredients in an effective amount to improve undesirable
conditions. As used herein "effective amount" refers to an amount
of a compound or composition having active ingredients such as
enzymes such as thrombin, vasoconstrictors such as epinephrine,
norepinephrine, angiotensin, or vasopressin, chemotherapeutic
agents such as fluorouracil (5-FU), and combinations of these
active agents in amounts sufficient to induce a particular positive
benefit to the polyp or tissue adjacent thereto. The positive
benefit can be health-related. In embodiments, the positive benefit
may be achieved by contacting tissue with a coagulation protein to
promote clotting and closure of the excised tissue. In embodiments,
the positive benefit may be achieved by contacting tissue with a
vasoconstrictor to reduce bleeding. In embodiments, the positive
benefit is achieved by contacting tissue with a chemotherapeutic
agent to kill cancerous cells.
[0058] The pH of the compositions can be adjusted to from about 4
to about 8. Agents suitable for adjusting the pH of the
compositions include, but are not limited to, buffering salts such
as NaH.sub.2PO.sub.4, NaHPO.sub.4, KH.sub.2PO.sub.4,
K.sub.2HPO.sub.4, NaHCO.sub.3, and Na.sub.2CO.sub.3, as well as
mineral acids and bases such as hydrochloric acid and sodium
hydroxide. The pH adjustment agents may be present in an amount of
from about 0.01 to about 5% by weight of the total composition. In
embodiments, the pH adjustment agent may be present in an amount of
from about 0.1 to about 1% by weight of the total composition.
[0059] In embodiments, the cannulas of the present disclosure may
be utilized to introduce a composition for use in endoscopic
polypectomy. Where utilized in a polypectomy procedure,
compositions may be applied to the submucosa of one or more polyps
to improve presentation of the polyp and make the polyp easier to
capture with an endoscopic instrument such as a snare. For example,
compositions having one or more thermoreversible and/or thermally
responsive polymers may be injected into the submucosa of a polyp
to improve its presentation.
[0060] The use of a thermally responsive polymer in compositions of
the present disclosure provides the ability to deliver or inject a
liquid, gel-on-contact material to the submucosa of one or more
polyps to promote removal thereof. As used herein, a gel refers to
a semisolid or semi-rigid system including a network of solid
aggregates in which liquid is held. By using a liquid delivery, it
is possible to quickly and efficiently treat a polyp with gelation
upon delivery to the warm tissues. By introducing such materials by
way of a multi-lumen cannula possessing a coolant in one cannula,
premature gelling of these polymers may be avoided.
[0061] In embodiments, compositions in accordance with the present
disclosure may be shear thinning and show a decrease in viscosity
with increasing rate of shear. Such shear thinning embodiments may
be suitable for injection into the submucosa of one or more polyps
in a highly viscosity state such as a gel at pre-treatment
temperatures. The application of highly viscous shear thinning
compositions in accordance with the present disclosure provide the
benefit of reducing and/or eliminating time needed for low
viscosity compositions to become highly viscous upon warming. In
embodiments, highly viscous shear thinning compositions at the
pretreatment temperature may become even more viscous at the
treatment temperature. In embodiments, use of a shear thinning
composition may reduce and/or eliminate a warming step needed to
thicken the compositions.
[0062] Polyps requiring removal may be pre-treated with one or more
compositions in accordance with the present disclosure which
include solvents and one or more polymers such as thermoreversible
polymers and/or thermally responsive viscosity modifiers. These
compositions may be in a low viscosity state at a pre-treatment
temperature and a higher viscosity or gel state at a treatment
temperature that is higher than the pre-treatment temperature. In
some embodiments additives may be included in the compositions of
the present disclosure to further adjust the temperature at which
the composition forms a gel.
[0063] Preconditioning polyps by injecting the compositions in
accordance with the present disclosure into the submucosa of one or
more polyps may enhance the benefits of polypectomy, for example,
by raising the polyps with a composition that gels or becomes more
viscous when heated or applied to a patient's warm body, and/or
does not readily escape polyps after initial incision thereof. Such
preconditioning further improves the presentation of a polyp making
it easier to grab and/or snare during excision.
[0064] In addition, treatment regimens in accordance with the
present disclosure may improve a passage blocked by one or more
polyps, and/or facilitate the removal of tissue having a propensity
to develop into a cancerous lesion. Compositions in accordance with
the present disclosure, at a pretreatment temperature and in a low
viscosity state prior to being injected, may be injected into the
submucosa of one or more polyps and allowed to warm to the
treatment temperature such that the compositions increase in
viscosity to a higher viscosity state such as a gel. In
embodiments, the viscosity of the compositions in accordance with
the present disclosure at the treatment temperature may be higher
then the viscosity of the compositions at the pre-treatment
temperature. Treatment may then continue by removing the one or
more polyps while the more viscous compositions in accordance with
the present disclosure remain substantially in the submucosa and to
some extent in the polyp.
[0065] The various constituents of the compositions in accordance
with the present disclosure may be combined with numerous
ingredients to form products to be applied to the polyp, or other
tissues of humans or other mammals.
[0066] It will be appreciated that various of the above-disclosed
and other features and functions, or alternatives thereof, may be
desirably combined into many other different systems or
applications. Also that various presently unforeseen or
unanticipated alternatives, modifications, variations or
improvements therein may be subsequently made by those skilled in
the art which are also intended to be encompassed by the following
claims. Unless specifically recited in a claim, steps or components
of claims should not be implied or imported from the specification
or any other claims as to any particular order, number, position,
size, shape, angle, color, or material.
* * * * *