U.S. patent application number 17/415775 was filed with the patent office on 2022-03-03 for hydrogel composition for mucosal lifting procedures within lumenal anatomical structures.
This patent application is currently assigned to QMARK MEDICAL INC.. The applicant listed for this patent is QMARK MEDICAL INC.. Invention is credited to Patrick H. RUANE, Sameer SHARMA.
Application Number | 20220062498 17/415775 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-03 |
United States Patent
Application |
20220062498 |
Kind Code |
A1 |
RUANE; Patrick H. ; et
al. |
March 3, 2022 |
HYDROGEL COMPOSITION FOR MUCOSAL LIFTING PROCEDURES WITHIN LUMENAL
ANATOMICAL STRUCTURES
Abstract
An injectable medical composition includes an acrylate and a
solvent. The composition has a first viscosity at temperatures
below body temperature and a second viscosity at body temperature.
The first viscosity is lower than the second viscosity.
Inventors: |
RUANE; Patrick H.; (Dublin,
CA) ; SHARMA; Sameer; (New York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
QMARK MEDICAL INC. |
Saint Paul |
MN |
US |
|
|
Assignee: |
QMARK MEDICAL INC.
Saint Paul
MN
|
Appl. No.: |
17/415775 |
Filed: |
December 20, 2019 |
PCT Filed: |
December 20, 2019 |
PCT NO: |
PCT/US2019/067966 |
371 Date: |
June 18, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62784213 |
Dec 21, 2018 |
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International
Class: |
A61L 27/20 20060101
A61L027/20; A61K 31/738 20060101 A61K031/738; A61L 27/52 20060101
A61L027/52; A61L 27/54 20060101 A61L027/54; A61L 27/16 20060101
A61L027/16; A61L 27/18 20060101 A61L027/18 |
Claims
1. An injectable medical composition comprising: an acrylate and a
solvent; wherein the composition has a first viscosity at
temperatures below body temperature and a second viscosity at body
temperature, the first viscosity lower than the second
viscosity.
2. The injectable medical composition of claim 1, wherein the
composition is configured to be in a Newtonian state at
temperatures below body temperature and in a non-Newtonian state at
body temperature.
3. The injectable medical composition of claim 1, wherein the
acrylate comprises a poly(acrylic acid) copolymer.
4. The injectable medical composition of claim 3, wherein the
poly(acrylic acid) copolymer comprises allyl sucrose or allyl
pentaerythritol.
5. The injectable medical composition of claim 1, wherein the
composition further comprises poly(ethylene oxide)-b-poly(propylene
oxide)-b-poly(ethylene oxide).
6. The injectable medical composition of claim 1, wherein the
acrylate in the composition is between 1.9% and 2.5% w/v.
7. The injectable medical composition of claim 1, wherein body
temperature is 35.5.degree. C.-38.5.degree. C.
8. The injectable medical composition of claim 1, wherein the
second viscosity is less than 4 Pas at shear rates of up to 10
s-1.
9. The injectable medical composition of claim 1, wherein the
second viscosity is greater than 0.2 Pas at shear rates of up to 10
s-1.
10. The injectable medical composition of claim 1, the second
viscosity at a shear rate of 10 s-1 is at least 30% less than the
second viscosity at a shear rate of 1 s-1.
11. The injectable medical composition of claim 1, wherein a shear
stress of the composition at body temperature is less than 100 Pa
at a rate of 0.1 s-1.
12. The injectable medical composition of claim 1, wherein a
hardness of the composition at body temperature is between 1N and
10N.
13. The injectable medical composition of claim 1, wherein an
adhesiveness of the composition at body temperature is less than
10N.
14. The injectable medical composition of claim 1, wherein a
compressibility of the composition at body temperature is less than
10N.
15. The injectable medical composition of claim 1, wherein an
elasticity of the composition at body temperature is less than
10N.
16. The injectable medical composition of claim 1, wherein a
maximum mucosal detachment force of the composition at body
temperature is less than 5N.
17. The injectable medical composition of claim 1, wherein a
mucoadhesion force of the composition at body temperature is less
than 5 mJ/cm2.
18. The injectable medical composition of claim 1, wherein a work
of adhesion of the composition at body temperature is less than
5N.
19. The injectable medical composition of claim 1, wherein the
composition is configured to generate a mucosal lift when injected
submucosally, and wherein the mucosal lift retains over 60% of its
original height for over 60 minutes.
20. The injectable medical composition of claim 1, wherein the
composition is configured such that a 5-10 cc syringe filled with
the composition can be deposited within the submucosal space
through an endoscopic needle injector using less than 20 Kg force
in less than 90 seconds.
21. The injectable medical composition of claim 1, wherein the
viscosity of the composition is less than 800 mPas at 22.degree. C.
and greater than 2500 mPas at 37.degree. C.
22. The injectable medical composition of claim 1, wherein the
composition, after injection submucosally, is configured to limit a
transference of electrical energy to a deeper intestinal wall when
electrosurgery is applied.
22. The injectable medical composition of claim 1, wherein the
viscosity of the composition reduces to less than 100 mPas within
90 minutes of injection submucosally.
24. The injectable medical composition of claim 1, wherein the
composition exhibits a G' value of greater than 7000 Pas between
0.1-10.0 Hz at body temperature.
25. The injectable medical composition of claim 1, wherein the
composition exhibits a G'' value of greater than 1300 Pas. between
0.1-10.0 Hz at body temperature.
26. The injectable medical composition of claim 1, wherein the
composition is manufactured by mixing components thereof at a
temperature less than 10.degree. C.
27. The injectable medical composition of claim 1, wherein the
composition is manufactured by sequentially adding polymers to the
solvent under magnetic stirring at less than 250 rpm.
28. The injectable medical composition of claim 1, wherein the
composition is manufactured by pre-mixing polymers at 100 rpm for 1
minute prior to addition to addition of the solvent to affect the
final viscosity.
29. The injectable medical composition of claim 1, further
comprising polystyrene or other microspheres at a concentration of
4.2%, wherein the composition with the polystyrene or other
microspheres has a viscosity that is 12% higher than a composition
without the polystyrene or other microspheres.
30. The injectable medical composition of claim 1, further
comprising marking pigment, wherein the marking pigment allows for
visible identification of the composition upon injection for up to
60 days.
31. The injectable medical composition of claim 1, wherein the
polymer does not include poly(propylene oxide).
32. The injectable medical composition of claim 1, wherein the
polymer does not include poly(ethylene oxide).
33. The injectable medical composition of claim 1, wherein the
composition does not include an oily component.
34. The injectable composition of claim 1, wherein polymers
comprise about 1% to about 10% of the composition by weight.
35. The injectable medical composition of claim 1, wherein polymers
comprise about 2% to about 4% of the composition by weight.
35. The injectable medical composition of claim 1, wherein the
solvent comprises distilled water.
36. The injectable medical composition of claim 35, wherein the
solvent comprises carbonic acid or sodium acetate.
37. The injectable medical composition of claim 1, wherein a pH of
the composition is approximately 5.1-7.4.
38. The injectable medical composition of claim 1, further
comprising a coloring agent.
39. The injectable medical composition of claim 38, wherein the
coloring agent is a dye.
40. The injectable medical composition of claim 39, wherein the dye
is methylene blue.
41. A method of performing a surgical procedure at a surgical site
in mucosal tissue, the method comprising: injecting an aliquot of a
hydrogel composition to raise an outer mucosal layer of the mucosal
tissue a distance away from a submucosal layer at the surgical
site; maintaining the outer mucosal tissue layer at least 60% of
the distance away from the submucosal layer for at least one hour;
and performing the surgical procedure on the outer mucosal layer
during the maintaining step.
42. The method of claim 41, wherein the injecting step and
performing step are performed endoscopically.
43. The method of claim 41, wherein the hydrogel has lower
viscosity at a first temperature and higher viscosity at a second
temperature, the first temperature being lower than the second
temperature.
44. The method of claim 41, wherein the first temperature is room
temperature having a temperature range of approximately 20 to 25
degrees Celsius and the second temperature is body temperature
having a temperature range of approximately 35.5 to 38.5 degrees
Celsius.
45. The method of claim 41, further comprising maintaining the
outer mucosal tissue layer at least 90% of the distance away from
the submucosal layer for at least 90 minutes.
46. The method of any of claim 41, wherein the aliquot has a volume
of about 20 ml or less.
47. A method of performing a surgical procedure at a surgical site
in mucosal tissue, the method comprising: injecting an aliquot of
an hydrogel composition to raise an outer mucosal layer of the
mucosal tissue a distance away from a submucosal layer of the
mucosal tissue at the surgical site, wherein the hydrogel
composition has lower viscosity at a first temperature and higher
viscosity at a second temperature, the first temperature being
lower than the second temperature; maintaining the distance for at
least 90 min; and performing the dissection on the outer mucosal
layer.
48. The method of claim 47, wherein the first temperature is room
temperature having a temperature range of approximately 20 to 25
degrees Celsius and the second temperature is body temperature
having a temperature range of approximately 35.5 to 38.5 degrees
Celsius.
49. A method of using a hydrogel composition as a marking agent in
surgical procedure, the method comprising: injecting an aliquot of
a hydrogel composition at a surgical site to visually distinguish
the surgical site from surrounding tissue, wherein: the hydrogel
composition has lower viscosity at a first temperature and higher
viscosity at a second temperature, the first temperature being
lower than the second temperature; the hydrogel composition
comprises a polymer composition and a coloring agent; and the
hydrogel composition provides visual delineation of the surgical
site for at least 90 minutes; and performing the procedure at the
surgical site.
50. The method of claim 49, wherein the first temperature is room
temperature having a temperature range of approximately 20 to 25
degrees Celsius and the second temperature is body temperature.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/784,213, titled "Hydrogel Composition for
Mucosal Lifting Procedures within Lumenal Anatomical Structures,"
filed Dec. 21, 2018, the entirety of which is incorporated by
reference herein.
INCORPORATION BY REFERENCE
[0002] All publications and patent applications mentioned in this
specification are herein incorporated by reference in their
entirety to the same extent as if each individual publication or
patent application was specifically and individually indicated to
be incorporated by reference.
FIELD
[0003] The current invention relates to injectable hydrogel
formulations. More particularly, the present invention relates to
formulations that contain hydrogel particles that form networks
within certain temperature ranges.
BACKGROUND
[0004] Gelation is a complex process, and attempts to theoretically
quantify this have been attempted previously. During polymerization
(gelation), up to an infinite number of networks are produced. The
key issue in this process is bond formation, which in turn causes
cluster formation. The more clusters that are formed, gelation
occurs. If p corresponds to the probability of bond formation, pc
corresponds to the gel point. When p>pc, at least one infinite
polymer cluster appears, and a lattice appears. This process is
called percolation. Examples of real experimental parameters that
affect the probability of bond formation include temperature, pH,
concentration, polymer reaction extent, polymer-polymer
interactions, polymer-solvent interactions, polymer-co-solvent
interactions, and polymer-additive interactions.
[0005] Hydrogels exhibit a relatively large change in volume
pertaining to a small change in external stimuli, e.g.,
temperature, due to the formation of hydrogel polymer networks,
which in turn cause polymer swelling.
[0006] Numerous clinical circumstances may gain significant
advantage from the injection of hydrogel formulations. For example,
the technique of gastrointestinal submucosal injection - lifting
the overlying mucosa or "mucosal lift" - involves the therapeutic
introduction of hydrogel formulations into the submucosal space of
the intestine. The submucosa is a potential space between the
superficial mucosal and deeper muscle layer of the intestine, for
example, to either raise a mucosal lesion away from the muscle
layer to aid in lesion removal or to mark the intestine by
depositing a pigment in the intestinal wall to identify a
particular location. Long lasting, non-dissipating lifting (e.g.,
by a hydrogel formulation) is desirable for managing various
diseases, disorders and conditions. In fact, any lumenal structure,
i.e. any anatomical structure with a central lumen and a
multi-layered wall, could benefit from such an agent (e.g. lung,
urological and gynecological).
[0007] In a typical mucosal lifting procedure that includes
injection of the formulation into the submucosal space to lift the
mucosa away from the deeper muscle wall (see FIG. 1), an endoscope
is first inserted into the patient's mouth or anus and navigated to
the area of interest. The area of interest may include, but is not
limited to, a site of pathological abnormality, e.g., adenomatous
polyps or a site of previous pathology, e.g., where a previous
surgical procedure was performed. The area around the abnormality
is then mucosally punctured using a long needle injector catheter,
typically over two meters in length, which is placed inside the
endoscope working channel.
[0008] The hydrogel formulation is transferred into the submucosal
space under the lesion, typically via depressing a syringe plunger
in which the hydrogel formulation is loaded. Appropriate lifting of
the pathology is confirmed visually by the clinician, typically
through the lifting of the mucosa. This lifting adds a degree of
safety for surgical removal of the lesion by providing a "cushion"
or "bleb," i.e., a separation of the mucosal surface and the muscle
wall, thus reducing the risk of perforation, i.e., breach of the
muscle layer of the intestine and subsequent passage of fecal
contents inside the peritoneal surface of the patient. The
peritoneal surface is sterile, thus contamination with fecal
contents is typically catastrophic.
[0009] In a typical marking procedure, at the area of interest
either proximally or distally and either prior to or after the
lifting procedure, the submucosal space is again injected (this
time with a submucosal injection formulation that loaded with
pigment). The marking formulation and pigment are then deposited
through the long endoscopic needle injector catheter.
[0010] The type of mucosal lifting formulation is chosen, for
example, based on the size of the pathology, location of pathology
within the gastrointestinal tract, and whether or not
electrocautery will be used. Electrocautery refers to the use of
electrical energy to either incise or cauterize the tissue.
Further, the submucosal marking formulation is chosen based on
whether the clinician wishes to mark the intestinal area for
referral of the patient to another clinician or whether that same
clinician wishes to re-examine the patient at a later date to
determine cure or recurrence of the pathology.
[0011] Various non-polymer based and polymer-based mucosal lifting
and marking formulations are currently employed in clinical
practice. These formulations are typically introduced to the
location of the intended lifting or marking through long needle
catheters, such as needle catheters up to 240 cm long and between
22-25 gauge in diameter. Due to the long length and small diameter
of the long endoscopic needle catheter, usable lifting and marking
agents are typically Newtonian in behavior i.e. liquid-like. The
materials that have been used commercially for lifting procedures
include 0.9% normal saline (sodium chloride dissolved in water for
injection), 6% hydroxyethylstarch (e.g. Hetastarch.TM.)
[0012] Similar Newtonian fluids have been used in mucosal lifting
procedures to increase the formulation submucosal residence time
after delivery, i.e., to reduce dissipation. For instance, human
albumin solution and dextrose solution have been used as mucosal
lifting agents by employing higher solution osmolality and thus
theoretically retaining water in the submucosal space for longer
periods of time. The difficulty with this approach is the
observation that the mucosal lift is not durable due to rapid
dissipation, reducing the degree of mucosa lift and increasing the
risk of muscle perforation. Injected submucosal agent rapid
dissipation also requires multiple repeated injections of the agent
by the clinician which increases the procedure time and cost. In
the case of marking agents, such as India ink (SPOT.TM., GI supply)
and methylene blue, dissipation of the agent leads to inaccurate
marking and sometimes disappearance of the marking pigment all
together.
[0013] In an attempt to improve the lifting durability of the
mucosal lifting agent and decrease the rate of dissipation, agents
with increased viscosity have been used, e.g., hyaluronic acid and
methylcellulose. However, problems have been encountered pertaining
to the high injection forces required to pass highly viscous agents
within the long, narrow endoscopic needle injector catheters. It is
also known that polymer-based purified or microemulsion agents for
lifting procedures (e.g. LeGoo-Endo.TM. or Eleview.TM.) have been
used. However, these agents exhibit Newtonian behavior within
parameters inside of the ideal required operative range, i.e. these
agents exhibit liquid characteristics up to 40 degrees Celsius,
which is significantly above normal physiological body temperature
of 37C. Eleview.TM. also exhibits several undesirable
characteristics in the field of adenomatous polyp removal, such as
leakage of the agent upon electrosurgical incision, thereby
hampering the clinician's view of the procedure.
[0014] Therefore, the current state of the art has clear
limitations and can be summarized by the following: [0015] 1. Rapid
dissipation, i.e., rapid absorption of the agent into the
surrounding tissues over time decreasing mucosal lift (or dome
height), corresponding to decrease of the submucosal `cushion` or
`bleb`. [0016] 2. Poor marking pigment accuracy (related to fast
dissipation) [0017] 3. Leakage of agent when performing therapeutic
procedures, e.g., incision to the intestinal mucosa using
electrosurgery causes the agent to leak out of the submucosal space
[0018] 4. Bubbling of agent when electrosurgery is applied, leading
to impaired view of the surgical operating field. [0019] 5. High
injection forces required to inject viscous fluid along long
endoscopic needle injectors (up to 240 cm in length and less than
0.5 mm in diameter), rendering single handed operation
impossible.
[0020] A mucosal lifting agent that addresses some or all of these
limitations is therefore desired.
SUMMARY OF THE DISCLOSURE
[0021] Described herein are hydrogel compositions that are
temperature sensitive and can be made of a hydrogel (i.e., a
natural or synthetic network of polymer chains that are strongly
hydrophilic (containing up to 99.9% water)). The hydrogels can have
a low viscosity while passing through the catheter to make it
easier for the physician or healthcare provider to apply force to
the syringe by hand to deliver the hydrogel to the target location.
Further, the increase in temperature of the hydrogel upon injection
into the body can result in an increased viscosity when placed in
the submucosal wall. The increased viscosity can allow the hydrogel
to stay within the injection site for a longer period of time,
thereby improving the efficiency of the surgical procedure
(multiple injections may not be required as is required with the
prior art compositions).
[0022] In general, in one embodiment, an injectable medical
composition includes an acrylate and a solvent. The composition has
a first viscosity at temperatures below body temperature and a
second viscosity at body temperature. The first viscosity is lower
than the second viscosity.
[0023] This and other embodiments can include one or more of the
following features. The composition can be configured to be in a
Newtonian state at temperatures below body temperature and in a
non-Newtonian state at body temperature. The acrylate can include a
poly(acrylic acid) copolymer. The poly(acrylic acid) copolymer can
include allyl sucrose or allyl pentaerythritol. The composition can
further include poly(ethylene oxide)- b- poly(propylene
oxide)-b-poly(ethylene oxide). The acrylate in the composition can
be between 1.9% and 02.5% w/v. Body temperature can be 35.5.degree.
C.-38.5.degree. C. The second viscosity can be less than 4 Pas at
shear rates of up to 10 s-1. The second viscosity can be greater
than 0.2 Pas at shear rates of up to 10 s-1. The second viscosity
at a shear rate of 10 s-1 can be at least 30% less than the second
viscosity at a shear rate of 1 s-1. A shear stress of the
composition at body temperature can be less than 100 Pa at a rate
of 0.1 s-1. A hardness of the composition at body temperature can
be between 1N and 10N. An adhesiveness of the composition at body
temperature can be less than 10N. A compressibility of the
composition at body temperature can be less than 10N. An elasticity
of the composition at body temperature can be less than 10N. A
maximum mucosal detachment force of the composition at body
temperature can be less than 5N. A mucoadhesion force of the
composition at body temperature can be less than 5 mJ/cm2. A work
of adhesion of the composition at body temperature can be less than
5N. The composition can be configured to generate a mucosal lift
when injected submucosally, and the mucosal lift can retain over
60% of its original height for over 60 minutes. Contents of a 5-10
cc syringe filled with the composition can be deposited within the
submucosal space through an endoscopic needle injector, using less
than 20 Kg force in less than 90 seconds. The viscosity of the
composition can be less than 800 mPas at 22.degree. C. and greater
than 2500 mPas at 37.degree. C. The composition, after injection
submucosally, can be configured to limit a transference of
electrical energy to a deeper intestinal wall when electrosurgery
is applied. The viscosity of the composition can reduce to less
than 100 mPas within 90 minutes of injection submucosally. The
composition can exhibit a G' value of greater than 7000 Pas between
0.1-10.0 Hz at body temperature. The composition can exhibit a G''
value of greater than 1300 Pas. between 0.1-10.0 Hz at body
temperature. The composition can be manufactured by mixing
components thereof at a temperature less than 10.degree. C. The
composition can be manufactured by sequentially adding polymers to
the solvent under magnetic stirring at less than 250 rpm. The
composition can be manufactured by pre-mixing polymers at 100 rpm
for 1 minute prior to addition to addition of the solvent to affect
the final viscosity. The injectable medical composition can further
include polystyrene or other microspheres at a concentration of
4.2%. The composition with the polystyrene or other microspheres
can have a viscosity that is 12% higher than a composition without
the polystyrene or other microspheres. The injectable medical
composition can further include a marking pigment. The marking
pigment can allow for visible identification of the composition
upon injection for up to 60 days. The polymer may not include
poly(propylene oxide). The polymer may not include poly(ethylene
oxide). The composition may not include an oily component. Polymers
can include about 1% to about 10% of the composition by weight.
Polymers can include about 2% to about 4% of the composition by
weight. The solvent can include distilled water. The solvent can
include carbonic acid or sodium acetate. A pH of the composition
can be approximately 5.1-7.4. The injectable medical composition
can further include a coloring agent. The coloring agent can be a
dye. The dye can be methylene blue.
[0024] In general, in one embodiment, a method of performing a
surgical procedure at a surgical site in mucosal tissue includes
(1) injecting an aliquot of a hydrogel composition to raise an
outer mucosal layer of the mucosal tissue a distance away from a
submucosal layer at the surgical site, (2) maintaining the outer
mucosal tissue layer at least 60% of the distance away from the
submucosal layer for at least one hour, and (3) performing the
surgical procedure on the outer mucosal layer during the
maintaining step.
[0025] This and other embodiments can include one or more of the
following features. The injecting step and performing step can be
performed endoscopically. The hydrogel can have lower viscosity at
a first temperature and higher viscosity at a second temperature
where the first temperature is lower than the second temperature.
The first temperature can be room temperature (which can have a
temperature range of approximately 20 to 25 degrees Celsius), and
the second temperature can body temperature (which can have a
temperature range of approximately 35.5 to 38.5 degrees Celsius).
Injecting an aliquot can further include maintaining the outer
mucosal tissue layer at least 90% of the distance away from the
submucosal layer for at least 90min . The aliquot can have a volume
of about 20 ml or less.
[0026] In general, in one embodiment, a method of performing a
surgical procedure at a surgical site in mucosal tissue includes
(1) injecting an aliquot of an hydrogel composition to raise an
outer mucosal layer of the mucosal tissue a distance away from a
submucosal layer of the mucosal tissue at the surgical site where
he hydrogel composition has lower viscosity at a first temperature
and higher viscosity at a second temperature, the first temperature
being lower than the second temperature, (2) maintaining the
distance for at least 90min, and (3) performing the dissection on
the outer mucosal layer.
[0027] This and other embodiments can include one or more of the
following features. The first temperature can be room temperature
having a temperature range of approximately 20 to 25 degrees
Celsius and the second temperature is body temperature having a
temperature range of approximately 35.5 to 38.5 degrees Celsius.
Wherein the distance is maintained for at least four hours.
[0028] In general, in one embodiment, a method of using a hydrogel
composition as a marking agent in surgical procedure includes (1)
injecting an aliquot of a hydrogel composition at a surgical site
to visually distinguish the surgical site from surrounding tissue,
where the hydrogel composition has lower viscosity at a first
temperature and higher viscosity at a second temperature and where
the first temperature is lower than the second temperature, (2)
maintaining visual delineation of the surgical site for at least 90
minutes, and (3) performing the procedure at the surgical site. The
hydrogel composition includes a polymer composition and a coloring
agent.
[0029] This and other embodiments can include one or more of the
following features. The first temperature can be room temperature
having a temperature range of approximately 20 to 25 degrees
Celsius and the second temperature is body temperature. Wherein the
hydrogel composition provides visual delineation for at least four
hours.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] The novel features of the invention are set forth with
particularity in the claims that follow. A better understanding of
the features and advantages of the present invention will be
obtained by reference to the following detailed description that
sets forth illustrative embodiments, in which the principles of the
invention are utilized, and the accompanying drawings of which:
[0031] FIG. 1 shows injection of an agent into the submucosal space
of the intestine via an endoscopic needle injector catheter passed
through the working channel of the endoscope.
[0032] FIG. 2 shows the chemical structure of a carbomer.
[0033] FIG. 3 shows the chemical structure of a PEO-PPO-PEO
triblock copolymer.
[0034] FIG. 4 shows results of a flow sweep analysis for a hydrogel
formulation relative to controls.
[0035] FIG. 5 shows results of viscosity analysis for a hydrogel
formulation over 1 hour at 37.degree. C. under constant shear rate
of 10/s to simulate submucosal space.
[0036] FIG. 6 shows results of viscoelastic property analysis for a
hydrogel formulation relative to controls at 37.degree. C.
[0037] FIG. 7 shows results of flow sweep analysis for a hydrogel
formulation with two different microbead percentages at 37.degree.
C.
[0038] FIG. 8 shows results of viscoelastic property analysis for a
hydrogel formulation with and without microbeads at 37.degree.
C.
[0039] FIG. 9 shows use of a hydrogel relative to saline and
Eleview.TM. over one hour after injection at 37.degree. C.
[0040] FIG. 10 shows height loss after injection for a hydrogel
formulation relative to controls one hour after injection at
37.degree. C.
[0041] FIG. 11 shows surface area change for a hydrogel formulation
relative to controls over one hour at 37.degree. C.
[0042] FIG. 12 shows the pigmented area of hydrogel formulations
relative to controls.
[0043] FIGS. 13A-13O show the lifting of various hydrogel
formulations relative to controls at 0 min, 15 min, 30 min, 45 min,
and 60 min.
DETAILED DESCRIPTION
[0044] Described herein are injectable formulations (also referred
to herein as "hydrogel" or "hydrogel formulation") that contain
temperature-sensitive hydrogel particles. The hydrogel may exhibit
Newtonian behavior below normal body temperature and/or may exhibit
non-Newtonian (viscoelastic/gelling) behavior above normal body
temperature. Such injectable formulations can be used, for example,
in conjunction with endoscopic medical procedures to act as mucosal
lifting agents. Thus, the mucosal lifting agents can exhibit
Newtonian behavior at temperatures less that 37.degree. C. and
exhibit non-Newtonian behavior at temperatures at or above
37.degree. C.
[0045] The hydrogels described herein can be endoscopically
injected into the submucosal space, elevating mucosally based
lesions away from the underlying layers of the intestinal wall and
introducing a margin of safety for lesion removal. The hydrogels
can advantageously provide enough separation of the layers for a
sufficient time for the endoscopic procedure to be performed.
Additionally, the hydrogels described herein can advantageously
maintain their shape during the entire or nearly the entire
procedure. The hydrogels described herein can act as marking and
cushioning agents that are safe and provide long-lasting separation
without diffusing into the surrounding areas. Additionally, the
hydrogels can be easily transferred from an injection device (e.g.,
a syringe) to the treatment site. In some embodiments, the
hydrogels are less viscous at ambient temperatures than at body
temperature. Additionally, the hydrogels can remain in the less
viscous state as they travel from the injection device to the
treatment site so that the entirety of the hydrogel formulation may
be delivered to the subject prior to a change in viscosity of the
composition.
[0046] The hydrogel formulations having Newtonian characteristics
below the normal body temperature can be injected into the body of
a subject. Subjects can include vertebrate subjects, particularly
humans and various animals including pigs. By injecting the
hydrogel formulation into the body at a temperature that is below
that of the Newtonian to non-Newtonian change temperature, the
formulation may be injected into the subject in a constricted
morphology. Upon warming in the body to physiological temperature,
however, the polymers can become agitated, for example, increasing
the likelihood of bond formation, or network formation, ultimately
producing non-Newtonian characteristics.
[0047] The hydrogel formulations described herein can include
acrylates and/or poloxamers (homopolymers and block copolymers,
respectively), both of which can advantageously alter their
swelling upon change of temperature. In one exemplary embodiment,
the hydrogel formulation includes poly(acrylic acid) (PAA)
copolymers modified with block-copolymers of poly(ethylene oxide)
(PEO) and poly(propylene oxide) (PPO). For example, poly(acrylic
acid) can be bonded onto a PEO-PPO-PEO triblock (e.g.,
Pluronic.RTM.) backbone via dispersion polymerization. The chemical
structure of a PEO-PPO-PEO triblock copolymer is shown in FIG. 3.
Initial optimization of the synthesis can define appropriate levels
of initial loading of acrylic acid and PEO-PPO-PEO triblock
copolymer, with a mixture of
2,2'-azobis(2,4-dimethylpentanenitrile) and lauroyl peroxide as an
initiator system. The synthesis can result in a copolymer with low
residual monomer content and a very high degree of bonding between
PEO-PPO-PEO triblock copolymer and PAA. Diluted aqueous solutions
of PEO-PPO-PEO triblock copolymer-g-PAA exhibit rapid
thermogelation.
[0048] In some embodiments, the hydrogel formulations described
herein can include a carbomer, such as Carbopol.RTM.. Carbomers are
synthetic high-molecular-weight polyacrylic acids cross-linked with
allyl sucrose or allyl pentaerythritol and contain between 56 and
68% w/w carboxylic acid groups. The chemical structure of a
carbomer is shown in FIG. 2. In some embodiments, the hydrogel
formulations can additionally include a non-ionic triblock
copolymer of poly(ethylene oxide)-b-poly(propylene
oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO), such as Pluronic.RTM.
poloxamer.
[0049] In some embodiments, the hydrogel compositions described
herein can be administered within the submucosal space of the human
intestine, such as for removal of a polyp via Endoscopic Mucosal
Resection (EMR) or Endoscopic Submucosal Dissection (ESD).
Exemplary procedural steps to deposit the disclosed hydrogel
formulation(s) into the submucosal space of the human intestine are
as follows. A 5 cc-10 cc syringe (equipped with a luer lock) can be
filled with the hydrogel formulation and capped and sterilized
("the device"). The device can be opened and connected to a
commercially available endoscopic needle injector via the luer
connector (e.g., a 240 cm, 2.8 mm diameter catheter with a 22-25 G
needle at its tip). The needle injector can be primed with the
device, i.e., by injecting up to 2 cc within the catheter so that
hydrogel formulation appears at the needle tip. The needle injector
tip can be deployed into the location where the device is to be
injected i.e. the submucosal space. Upon appropriate location, the
operator or operating assistant can depress the syringe plunger to
inject less than lcc of the hydrogel formulation to confirm
placement. After positive confirmation from the operator, the
desired amount of hydrogel formulation can be injected into the
submucosal space. After injection is completed, the needle can be
resheathed into the catheter and the endoscopic needle injector
removed from the endoscope in it's entirety. The device syringe can
then be disconnected from the needle injector. The entire device
can be disposed of.
[0050] The hydrogels described herein can advantageously be used
for injection-assisted EMR and can be safe, inexpensive, non-toxic,
readily available, easy to inject and capable of providing a high,
long-lasting submucosal cushion. In some embodiments, the hydrogels
can be colored (e.g., with a dye) that can aid with distinguishing
more easily the depth of the muscolaris mucosa, thereby avoiding
undue perforation during techniques such as ESD. In some
embodiments, the pigment can include methylene blue or FDandC#1.
The amount of pigment can be, for example, less than 20 cc, such as
less than 10 cc, such as approximately cc of 1% pigment per 100 cc
of solution. Keeping the amount of pigment (e.g., methylene blue)
low can increase the thermosensitive effects of the hydrogel.
[0051] The hydrogels described herein can have minimal diffusion
within the intestinal walls, resulting in sustained height of the
mucosal lesion away from deep layers and maintaining 75%-100%, such
as 90%-100%, of its original height over a reasonable amount of
time. Further, the hydrogels can be non-toxic but also
biocompatible and can produce little or no local or systematic side
effects. The hydrogels can be configured so as to not conduct heat
or electricity, which may interfere with the endoscopic procedure
being performed. Further, the hydrogels can be easy to handle at or
below room temperature and can be of sufficiently low viscosity to
be injected over a long endoscopic delivery system (e.g. greater
than 220 cm). The hydrogels described herein can be highly
compatible with therapeutic flexible endoscopies (FE) and can
improve patient outcomes by reducing risk and speeding up recovery
times, particularly for patients with benign diseases that would
otherwise require major traditional surgery.
[0052] In use, the hydrogels described herein can advantageously
expand the submucosal layer of the intestinal where the mucosa is
elevated away from underlying layers of the intestinal wall and
bulges into the intestinal lumen, permitting better visualization
of a lesion and enhanced options for removal or sampling of
pathology.
[0053] In some embodiments, the hydrogel compositions described
herein can include one or more of the following features: [0054] 1.
The formulations can retain 50-90%, such as approximately 60% of
the original injected dome height lhr after injection. [0055] 2.
The formulations can be delivered via an off the shelf syringe. The
contents (e.g., up to 5-10 cc and/or a needle of at least 100 cm or
25 G) can be expelled into the submucosal space within 90 seconds
using up to 20 Kg force. [0056] 3. The formulations can have a
viscosity of approximately 800 mPas at 22.degree. C. and
approximately 2500 mPas at 37.degree. C. [0057] 4. The formulations
can have a hardness when injected into the submucosal space at
37.degree. C. that exceeds 1N (e.g., is between 1N and 10N). [0058]
5. The formulations can have a mucoadhesion that exceeds 5 mJ/cm2
at 37.degree. C. [0059] 6. The formulations may not produce
excessive bubbles when electrosurgery is applied. [0060] 7. The
formulations may reduce to less than 100 mPas within 90 minutes of
injection. [0061] 8. The formulations can dissipate within 360
minutes at 37.degree. C. [0062] 9. The formulations may exhibit a
G' greater than 7000 Pas and a G'' greater than 1300 Pas. [0063]
10. The formulations can include a pigment that permits
identification of the injected area in addition to the anatomical
structures of the submucosal space.
[0064] In some embodiments, the hydrogel compounds described herein
may include additional bio-compatible agents. For example, in some
instances, a therapeutic agent may be included. By way of example
only, therapeutic agents may include a non-steroidal
anti-inflammatory agent, a steroid, an analgesic, or an
antimicrobial agent. In other examples, the hydrogel composition
may include an anesthetic.
[0065] The hydrogels described herein can include a small
percentage of a polymer or hydrogel (e.g. a carbomer and
PEO-PPO-PEO triblock copolymer). In some instances, the hydrogel
composition includes 0.2%, 0.3%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.4%,
1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%,
4%, 4.2%, 4.4%, 4.6%, 4.8%, or 5% of a carbomer, such as Carbopol
ETD. In other variations, the hydrogel composition includes 0.2%,
0.3%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%,
2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%,
or 5% of a carbomer, such as Carbopol NF. In yet other examples,
the hydrogel composition may include 10%, 12%, 14%, 16%, 18%, 20%,
22%, 24%, 26%, 28%, 30%, 32%, or 34% PEO-PPO-PEO triblock
copolymer, such as Pluronic 127. In some other variations, a
combination of various hydrogels may be used. For example, a
combination of a carbomer and PEO-PPO-PEO triblock copolymer may be
used. The combination of a carbomer and PEO-PPO-PEO triblock
copolymer may be 0.2% and 14%, 0.3% and 14%, 0.4% and 14%, 0.2% and
13%, 0.2 and 15%, 0.4% and 14%, 0.6% and 14%, 0.3% and 13%, 0.3%
and 15%, 0.3% and 28%, 0.3% and 27%, 0.3% and 29%, 0.4% and 27%,
0.4% and 28%, 0.4% and 29%, 0.5% and 27%, 0.5% and 28%, 0.5% and
29%, 0.6% and 27%, 0.6% and 28%, or 0.6% and 29% respectively.
[0066] The hydrogel formulations described herein can include any
suitable carbomer or PEO-PPO-PEO triblock copolymer agent depending
on the desired hydrogel formulation characteristics. These include,
but are not limited to, Poloxamer 188, Carbopol 971P NF, Carbopol
974P NF, Carbopol AA-1 and Carbopol ETD2020. The concentrations of
the aforementioned polymers and co-polymers can range within the
limits of 1, 2, 5, 10, or 20 to 30 g/100 mL of solvent and
co-solvent. In addition, the concentrations can range 0.01, 0.01,
0.5 to 0.9 per 100 mL.
[0067] In some embodiments, a buffer may be used to stabilize the
polymer components and or/solution components. Such buffers may be,
for example, carbonic acid or sodium acetate buffer solution. These
buffers can, for example, help stabilize the solution when
electrosurgical tools are used.
[0068] In one exemplary embodiment, the hydrogel can include
poloxamer (5%), carbomer (2.5%), xanthum gum thickener (1%),
sterile water (74%), pigment (1%) and a buffer (25%).
[0069] A plurality of exemplary hydrogel formulations and their
methods of manufacture are described herein.
Experimental Study 1
[0070] In a first experimental study, a hydrogel formulation as
described was produced and its characteristics (e.g., gel
transition temperature, flow deformation, viscosity, storage
modulus, loss modulus, hardness, mucoadhesion, conductivity, and
dome height) analyzed. The hydrogel formulation included 50 mL of
water, lg of Poloxamer 407, 0.1g of carbomer (Carbopol 971P), and
0.001 g of methylene blue. In a first embodiment (formulation A),
the poloxamer and carbopol were sequentially mixed. In a second
embodiment (formulation B), the poloxamer and carbopol were
pre-mixed. The method of producing the hydrogel formulation
included: [0071] 1) In a stainless steel or other suitable vessel
provided with a suitable stirrer, (the stirrer weighed 5.88 g per
100 cc), at 50-100 rpm, 50 mL of water for injection was loaded.
Then, 50 mL of sodium chloride was added. The mixture was kept
under constant temperature control between 3 to 10.degree. C. Then,
lg of Poloxamer 407 was added under stirring until completely
submerged. Then 0.1 g of Carbopol 971P was added until completely
submerged. The mixture was kept under stirring for 1 hour. This is
termed sequential mixing (formulation A); or In a stainless steel
or other suitable vessel provided with a suitable stirrer at 50-100
rpm, 50 mL of water for injection was loaded. Then, 50mL of sodium
chloride is added. The mixture was kept under constant temperature
control between 3 to 10.degree. C. Then, 1 g of poloxamer 407 is
mixed with 0.1 g of Carbopol 971P at 10 rpm-100 rpm for 5 minutes.
The resulting mixture was then added to the water and sodium
chloride mixture. This is termed pre-mixing (formulation B). [0072]
1) The mixture was then removed from the temperature controlled
stirrer and placed in refrigeration 4.degree. C. for 24 hrs. [0073]
2) The mixture of step (2) was then warmed to 22.degree. C. (room
temperature). [0074] 3) The pH of the mixture was measured and it
is brought, if necessary, within the range 4.0-8.0, such as
5.0-7.5, such as 5.1-7.4 through addition of sodium hydroxide
0.01M. [0075] 4) After this, 0.001 g of methylene blue was added
under stirring. The mixture was kept under stirring until
homogeneity at 50-100 rpm. [0076] 5) The final composition was
filtered through a 0.40 .mu.m filter and packed in 5 cc syringes
and capped. The syringes (and formulation therein) were sterilized
with Ethylene oxide sterilization (ETO), electron beam
sterilization, or other methods of sterilization.
[0077] The hydrogel formulation was characterized based upon
solution gelation transition temperature (SGTT), flow and
deformation characteristics, viscosity change over time under
physiological conditions, the elastic modulus or loss modulus,
mechanical properties (e.g., hardness, compressibility,
cohesiveness, retraction force), adhesive force, electrical
conductive properties, performance upon addition of microbeads,
degree of mucosal lift, pigment marking, electrical conduction upon
application of electrosurgical energy, and pigment injection
accuracy over time. The experimental results pertaining to each of
these characteristics are summarized below.
[0078] The first characteristic analyzed was the Solution (Sol)
Gelation (Gel) Transition Temperature (SGTT) of the hydrogel
formulation. SGTT can be used as a key parameter in defining the
clinical suitability of a hydrogel formulation compositions as
disclosed herein. At SGTT, the properties of the hydrogel
formulation change from a liquid-like state (Newtonian) to a
solid-like state (non-Newtonian), which corresponds to significant
viscosity increase and mucosal lift. Advantageously, if the
hydrogel formulation can reach SGTT at 37.degree. C.+/-1-1.5, a
robust lift will be gained upon the formulation reaching body
physiological temperature.
[0079] To analyze the SGTT, a magnetic temperature controlled
stirring plate was used (TECA AHP-301MSP), allowing computer
controlled accurate temperature modulation. In this case, a
temperature ramp from 4 to 45.degree. C. was used, where the plate
was set to increase the temperature by 1C per minute. A 4.75 g
stirrer bar was placed in the bottom of either a 100 or 50 cc
beaker and set to 100 rpm. The temperature at which the stirrer bar
stopped was considered the formulation SGTT. Normal saline and
Eleview.TM. (a commercially available poloxamer emulsion) were used
as reference agents in this testing.
[0080] SGTT results of the formulations compared to reference
agents are shown in Table 1 below. As indicated, normal saline and
EleviewTM do not reach gelation viscosity at physiological
temperatures, whereas the formulation compositions disclosed herein
gel at physiological temperatures +/-1.5.degree. C.
TABLE-US-00001 TABLE 1 SGTT Agent SGTT (.degree. C.) Normal Saline
>45 Eleview .TM. >45 Hydrogel formulation (A) 35.8 Hydrogel
formulation (B) 37.9
[0081] The second characteristic analyzed was the flow and
deformation of the hydrogel formulation (with focus on absolute
viscosity). The in-vitro hydrogel formulation viscosity
determination can provide key information regarding hydrogel
resistance to gradual deformation by shear or tensile stress. For
liquids, it corresponds to the informal concept of "thickness,"
e.g. honey's viscosity is higher than that of water. This data can
give important information regarding the viscosity changes
exhibited by the formulations through external stimuli changes,
e.g., changes to viscosity according to temperature change.
Viscosity is a property which opposes the relative motion between
two surfaces of the fluid moving at different relative velocities.
In simple terms, viscosity designates the friction concerning the
fluid molecules. When fluid is forced through a tube, the fluid
composition particles generally move faster near the tube's axis
and slower near its walls. Therefore, some stress (such as a
pressure difference between the two ends of the tube) is needed to
overcome the friction between particle layers to keep the fluid
moving. For a given velocity pattern, the stress required is
proportional to the fluid's viscosity. In this situation, a
formulation with a viscosity similar to water at room temperature
and changing to a higher viscosity at body temperature would be
advantageous. This would be clinically relevant, as it indicates
the formulation would be injectable along the long thin endoscopic
needle injector catheters and subsequently increase its viscosity
once in the submucosal space of the hydrogel intestine (and exposed
to body temperature), thus providing a durable mucosal lift,
through reducing the probability of dissipation. Table 2 below
shows typical viscosity values.
TABLE-US-00002 TABLE 2 Viscosity Values Materials Viscosity (Pa s)
Air/Gas 0.00001 Water 0.001 Milk/Coffee 0.01 Olive oil 0.1 Glycerol
1 Liquid Honey 10 Molasses 100 Polymer Melt 1000 Asphalt Binder
100,000
[0082] To analyze flow and deformation, rheological analysis of the
hydrogel formulation were performed at 22.+-.0.1.degree. C. and
37.+-.0.1.degree. C. using an AR 2000 controlled stress/controlled
rate rheometer (TA instruments, New Jersey, USA), in flow mode, and
in conjunction with parallel steel plate geometry (40 mm diameter).
In continuous shear analysis, upward and downward flow curves for
each formulation were measured over shear rates ranging from
1-10.sup.5 s.sup.-1. Oscillatory analysis of each formulation under
examination was performed after determination of its linear
viscoelastic region at 22.+-.0.1.degree. C. and 37.+-.0.1.degree.
C., where stress was directly proportional to strain and the
storage modulus remained constant. Frequency sweep analysis was
performed over the frequency range of 0.1-10.0 Hz following
application of a constant stress and standard gap size was 0.1 mm
for each sample. Normal saline (Baxter, Deerfield, IL) and
Eleview.TM. (Aries Pharmaceuticals, California, USA) were used as
reference agents.
[0083] The resulting viscosity (based upon logarithmic flow sweep
analysis) is shown below in Table 3 and in FIG. 4.
TABLE-US-00003 TABLE 3 Viscosity relative to Temperature Viscosity
Viscosity (mPa s) (mPa s) Agent @ 22.degree. C. @ 37.degree. C.
Normal Saline 1.22 0.9 Eleview .TM. 6 3.8 Hydrogel formulation (A)
164 22022
All agents exhibited Newtonian (liquid) behavior at 22.degree. C.
Only the hydrogel formulation disclosed herein, however, exhibited
a viscosity change at 37.degree. C. (i.e., exhibited a
significantly higher viscosity, such as 10 times or more, 50 times
or more, 100 times or more, or 125 times or more higher, at
37.degree. C. relative to 22.degree. C.). This viscosity change is
important to ensure that the hydrogel formulation remains in place
during a procedure, such as mucosal lifting. In contrast, those
formulations with viscosities at the same level as saline (e.g.,
substantially consistent from 22.degree. C. to 37.degree. C.) would
be expected to dissipate rapidly and so perform poorly as a mucosal
lifting agent.
[0084] The third characteristic analyzed was viscosity change over
time under physiological conditions to simulate the submucosal
space residence time of the hydrogel. Determination of the in-vitro
rheological properties of the hydrogel over time offers key
information regarding hydrogel formulation behavior after
deposition into the chosen anatomical area, e.g., after injection
into the submucosal space of the intestine. A formulation with a
viscosity that decreases over time to that of something akin to
saline over 60-90 minutes would be advantageous, as this indicates
the formulation would provide a durable mucosal lift for the
typical procedure time, reducing the need for repeat injections and
risk of perforation of the muscle layer. This level of submucosal
residence time also ensures that the hydrogel formulation is not be
permanent and would therefore will not obstruct the intestinal
lumen.
[0085] To analyze the viscosity change over time, the hydrogel
formulation was rheologically analyzed at 37.+-.0.1.degree. C.
using an AR 2000 controlled stress/controlled rate rheometer (TA
instruments, New Jersey, USA), in flow mode, and in conjunction
with parallel steel plate geometry (40mm diameter). Viscosity was
measured over 60 minutes under a constant shear rate of 10/s
(simulating the submucosal space). The viscosity decay over time is
shown in Table 4 below and in FIG. 5. As shown, the formulation
advantageously dissipates to a viscosity similar to saline in
approximately 85 minutes.
TABLE-US-00004 TABLE 4 Viscosity relative to Temperature
x-intercept - y-intercept - time to reach 0 viscosity viscosity
Agent (mPa s) (seconds) R2 Hydrogel formulation (A) 22400 5101
0.89
[0086] The fourth characteristic analyzed was the complex
viscosity, including determining the elastic storage modulus (G')
and the loss modulus (G''). Determination of in vitro elastic and
storage rheological properties of the hydrogel gives key
information regarding the formulation's behavior upon application
of energy. This information predicts the performance of the
hydrogel in different phases of its life cycle, e.g., during shelf
storage, upon injection, and during submucosal space residence.
This analysis gives key information regarding the viscosity changes
and elastic behavior on temperature modulation.
[0087] The hydrogel formulations described herein can be a
viscoelastic material and therefore exhibit both viscous and
elastic behavior. Such viscoelastic materials can be considered a
combination of both ideal types of materials: purely viscous fluids
and ideally elastic solids. The flow properties of a purely viscous
material can be determined in a simple flow experiment. If the
material deforms at a constant rate the applied constant stress is
constant and described by a simple relationship known as Newton's
law. Such liquids are known as Newtonian fluids, and the material
constant is referred to as Newtonian viscosity. For an elastic
solid material (e.g., a steel spring or cross-linked rubber), a
simple linear relationship exists between the stress and the
strain. The material deforms instantaneously when subjected to a
sudden stress and the strain will remain constant until the stress
is removed. There is no loss of energy, and the solid will return
to its original shape (the deformation is fully reversible). The
material constant is the modulus of the material. The equation
relating the stress and the strain is known as Hooke's law. In
reality, most materials lie somewhere in-between these two
extremes.
[0088] The elastic or storage modulus defines gives information
about the amount of structure present in a material. It represents
the energy stored in the elastic structure of the sample. If it is
higher than the loss modulus, the material can be regarded as
mainly elastic, i.e,. the phase shift is below 45.degree.. The loss
modulus represents the viscous part or the amount of energy
dissipated in the sample. The "sum" of loss and storage modulus is
the so-called complex modulus G*. The complex viscosity .eta.* is
the standard parameter used in this case and can be calculated
directly from the complex modulus. For the uses described herein
(e.g., for mucosal lift), a hydrogel formulation with a high
storage and loss modulus with a corresponding higher complex
viscosity would be advantageous at body temperature. This would be
clinically relevant through the indication that the formulation has
significant viscoelastic properties and does not behave like a
liquid, therefore allowing the formulation to reside in the
submucosal space longer and provide a durable mucosal lift,
reducing the risk of perforation of the deep muscle layer.
[0089] To analyze the complex flow viscosity, rheological analysis
of the hydrogel formulation was performed both at 22.+-.0.1.degree.
C. and 37.+-.0.1.degree. C. using an AR 2000 controlled
stress/controlled rate rheometer (TA instruments, New Jersey, USA).
Oscillatory analysis of each formulation under examination was
performed after determination of its linear viscoelastic region at
22.+-.0.1.degree. C. and 37.+-.0.1.degree. C., where stress was
directly proportional to strain and the storage modulus remained
constant. Frequency sweep analysis was performed over the frequency
range of 0.1-10.0 Hz following application of a constant stress and
standard gap size was 0.1 mm for each sample. Storage modulus (G')
and loss modulus (G''), the complex viscosity (.eta.'), and the
loss tangent (tan .delta.) were determined. In each case, the
dynamic rheological properties of at least five replicates were
examined. Complex viscosity is not the same as apparent viscosity
and is a function of shear rate. Normal saline (Baxter, Deerfield,
Ill.) and Eleview.TM. (Aries Pharmaceuticals, California, USA) were
used as reference agents.
[0090] The viscoelastic properties of the hydrogel formulation
compared to reference agents are shown in Table 5 below and in FIG.
6. As can be seen, the hydrogel formulation shows significant
viscoelastic (non-Newtonian) behavior under physiological
conditions. In comparison, the reference agents showed no
characteristics of viscoelasticity at physiological parameters,
i.e., they remain liquid (Newtonian) at body temperature.
TABLE-US-00005 TABLE 5 Viscoelastic Properties G' G'' Complex
viscosity Tan Agent (Storage Modulus Pa) (Loss Modulus Pa) (mPa s)
(delta) Normal Saline -0.11 0.02 11 -0.18 Eleview .TM. -0.14 0.05
15 -0.37 Hydrogel formulation (A) 7560 1347 768857 0.18
[0091] The fifth characteristic analyzed included the various
mechanical properties of the hydrogel formulation. Determination of
in vitro mechanical properties of the hydrogel formulations can
give key information about the physical gel structure of the
hydrogel, e.g., hardness, compressibility, cohesiveness, retraction
force. Hardness refers to the resistance to localized plastic
deformation induced by either mechanical indentation or abrasion.
Hardness describes the formulations resistance to deformation when
an external physical force is applied to it, mimicking the external
electrosurgical device or even the endoscope placing force on it.
Compressibility refers to the measure of the relative volume change
of a fluid or solid as a response to a pressure (or mean stress)
change. Cohesiveness refers to the action or property of the
formulation molecules sticking together, being mutually attractive.
It is an intrinsic property of the hydrogel that is caused by the
shape and structure of its molecules, which makes the distribution
of orbiting electrons irregular when molecules get close to one
another. In other words, cohesion allows for surface tension.
Maximum retraction force is the force required to overcome the
surface tension of the hydrogel. Mechanical property information
can be used to predict the hydrogel formulation behavior in
different physiological and environmental conditions. A formulation
with a high hardness, compressibility and retraction force with a
low cohesiveness would be advantageous for use in submucosal
lifting, as these properties can enable the formulation to retain
its immediate post injection state and prevent leakage once incised
e.g. when using electrosurgery.
[0092] Texture profile analysis (TPA) can be applied for mechanical
characterization of semi-solid systems and gels. To determine these
mechanical properties, the analytical probe of the TPA machine can
be inserted into a semi-solid system to a defined depth, at a
defined rate and extracted out at define rate. The resulting change
in force can be plotted against time and provides the different
mechanical properties such as hardness and compressibility. Texture
profile analysis was performed using Software-controlled
penetrometer (TA-XT Plus, Stable Micro System, UK) equipped with 5
kg load cell in texture profile analysis (TPA) mode. The
formulations was transferred into a glass beaker (50 mL) at
37.degree. C. An analytical probe was twice inserted into the
formulation to a defined depth (15 mm) and at a defined rate (2
mm/s), allowing a delay period (15 s) between the end of the first
and beginning of the second compression. Mechanical parameters
(hardness, compressibility, cohesiveness and elasticity) were
derived from the resultant force-time curve. Experiments were
carried out at least three times. Normal Saline (Baxter, Deerfield,
Ill.) and Eleview.TM. (Aries Pharmaceuticals, California, USA) were
used as reference agents.
[0093] The mechanical properties of the hydrogel formulations
compared to reference agents are shown in Table 6 below. As shown,
the hydrogel formulation (both A and B) exhibited significantly
different mechanical properties than the reference agents,
including increased hardness (e.g., 10-20 times higher hardness),
compressibility (e.g., 20-30 higher compressibility), and
retraction force (e.g., 5-10 times higher retraction force). The
increased hardness indicates that the formulation will resist
deformation while the higher compressibility indicates that the
formulation will return to its original shape post application of
an external force. The higher maximum retraction force denotes the
increased force required to remove the agent upon residence in the
submucosal space. Taken together, this data indicates that, upon
injection into the submucosal space, the hydrogel formulation can
provide a more durable, consistent mucosal lift than the reference
agents.
TABLE-US-00006 TABLE 6 Mechanical Properties Max Agent Hardness
Compressibility Cohesiveness retraction Normal Saline 0.1 0.3 0.8
-0.02 Eleview .TM. 0.1 0.3 1 -0.02 Hydrogel formulation (A) 1.9 7.1
0.02 -1.5 Hydrogel formulation (B) 1.7 6.2 0.02 -1.2
[0094] The sixth characteristic analyzed was the adhesion (e.g.,
adhesion to the mucosa and submucosa. Mucoadhesive force is defined
as the force with which the hydrogel formulation binds to the
mucosal surface at physiological temperature (37.degree. C.). It is
useful in assessing the formulation potential to interact with a
mucosal surface and leakage behavior, e.g., after incision of the
mucosal surface with electrosurgery. The mucoadhesive properties of
the formulation can be determined by attaching mucous membrane
(natural origin, e.g., porcine tissue, or artificial, e.g., mucin
disks) to the bottom of the TPA analytical probe. In this
situation, a formulation with a high mucoadhesive force would be
advantageous, as a high mucoadhesive force will lead the
formulation to reside in the submucosal space longer without
leaking.
[0095] To show and compare the mucoadhesive strength of the
disclosed formulation, porcine rectal mucosa was used. Mucosal
tissue was obtained from newly sacrificed animals (<24hours).
Mucosa was separated from underlying tissues, washed, cut in
smaller pieces and rinsed carefully. The samples were frozen at
-20.degree. C. until used. The mucoadhesive properties of
formulations were evaluated with a 5 kg load cell using TA-XT Plus
texture analyzer. A tissue section that possessed 2 mm thickness
was taken from the inner part of the surface of the mucosal
membrane (or mucin disc) and it was attached to the lower end of
the probe (P 10 Perspex, .theta.: 10 mm) of the instrument with
cyanoacrylate glue. The gels were packed into a 50 cc beaker and
tests were conducted at 37.degree. C. The probe holding the mucosa
was lowered on to the surface of the gel with a constant speed of
0.1 mms-1 and a contact force of 0.2 N were applied. After keeping
in contact for 120 s, the probe was then moved vertically upward at
a constant speed of 0.1 mms.sup.-1. Maximum force (the detachment
force, F) was obtained from the force-distance graph. Tee area
under the curve (AUC) was calculated from force-distance plot as
the mucoadhesion (M). The equation given below was used to
calculate the work of mucoadhesion (mJ/cm2). Each experiment was
carried out five times and the results were evaluated
statistically. Normal saline (Baxter, Deerfield, Ill.) and
Eleview.TM. (Aries Pharmaceuticals, Califonia, USA) were used as
reference agents.
Work of mucoadhesion=AUC/r.sup.2 (mJ/cm.sup.2) where, .pi.2=the
area of the mucosal surface being in contact with gel.
[0096] The mucoadhesion of the hydrogel formulation (A and B)
compared to the reference agents is shown in Table 7 below. The
formulation embodiments disclosed herein exhibited significantly
higher mucoadhesion properties (e.g., 20-30 times higher
mucoadhesion) compared to the reference agents. This property is
advantageous, as the hydrogel formulations are therefore more
likely to reside within the intestinal submucosal space and provide
a more durable mucosal lift (e.g., upon incision with
electrosurgical tools).
TABLE-US-00007 TABLE 7 Mucoadhesion Mucoadhesion Agent
(mJ/cm.sup.2) Normal Saline 0.02 Eleview .TM. 0.02 Hydrogel
formulation (A) 5.3 Hydrogel formulation (B) 5.5
[0097] The seventh parameter analyzed was the electrical
conductivity of the hydrogel. It is expected that electrosurgical
may be applied in and around the hydrogel formulations injected
site of administration, e.g., under and around an intestinal
adenomatous polyp within the submucosal space. Hydrogel
formulations can be characterized as either conductive or insulator
in behavior. Purely conductive formulations permit conduction of
electrical energy through the material. Purely insulator
formulations permit no transmission of electrical energy.
Transmission of electrical energy is relevant in these embodiments
due to the use of electrosurgical energy in and around the lesion
for removal e.g. an intestinal polyp. An ideal agent will be as
much as an insulator as possible to prevent transmission of
electrosurgical energy to the deeper intestinal wall causing
immediate or delayed perforation. However, the formulation should
also allow local transmission of electrosurgical energy to provide
electrosurgical dissection via snare and endoscopic submucosal
dissection devices (Olympus Snaremaster.TM. Dualknife.TM. or
similar).
[0098] To analyze the conductivity, a magnetic stirring temperature
controllable plate was used (TECA AHP-301MSP) allowing computer
controlled accurate temperature modulation according to computer
program selection. In this case, a temperature hold at 37.degree.
C. was used. Once the temperature of the agent was confirmed to be
37.degree. C. for 5 minutes the probe of an Omega CDH-SD1 data
logging conductivity meter was placed. Conductivity was measure in
mS/cm. Normal saline (Baxter, Deerfield, Ill.) and Eleview.TM.
(Aries Pharmaceuticals, California, USA) were used as reference
agents.
[0099] The conductivity of disclosed hydrogel formulations compared
to reference agents is shown in Table 8 below. As shown, the
hydrogel is a relative insulator (i.e., shows 50-75 times higher
conductivity) compared to saline and Eleview.TM.. Insulator
characteristics can be favorable where electrosurgery energy is
used as to prevent damage to the muscle layer of the intestine and
immediate or delayed perforation.
TABLE-US-00008 TABLE 8 Conductivity Conductivity Agent (mS/cm)
Normal Saline 15 Eleview .TM. 6 3% sorbitol urological 0.1
irrigation fluid Hydrogel formulation (A) 0.27 Hydrogel formulation
(B) 0.26
[0100] The eighth characteristic analyzed was the change in
performance of the hydrogel upon the addition of microbeads.
Microbeads (coated or uncoated with additional materials, for
example but not limited by coagulants, antibacterials or metallic
coatings) can be added to the current hydrogel formulation
embodiment to provide additional characteristics such as increased
surface area for using less polymer, drug delivery e.g. antibiotics
and anticoagulants and radiological visibility amongst others. In
these experiments, polystyrene microbeads were used, however many
different types are available and may be used. The hydrogel
formulation may use the least amount of polymer as possible to
facilitate the lowest possible viscosity for injection and provide
increased surface area to allow polymeric networks to form (upon
hydrogel formulation warming). Clinically, this can result in an
injectable formulation that is easy to inject via a standard
syringe, particularly along the long endoscopic needle injector
catheters, at room temperature as well as a formulation that
exhibits improved gelling upon warming. In addition, the
cultivation of additional pharmaceutically derived properties may
be useful in many clinical situations.
[0101] To analyze the effect of microbeads, microbeads were mixed
into the hydrogel formulation according to % weight by volume.
Rheological analysis was then undertaken as described previously to
determine the viscosity.
[0102] Logarithmic flow sweep analysis of hydrogel formulations
with addition of microbeads is shown below in Table 9 and in FIG.
7. As shown, the addition of microbeads increases the absolute
viscosity.
TABLE-US-00009 TABLE 9 Viscosity with Microbeads Viscosity (mPa s)
@ Agent 37.degree. C./Shear 10 s.sup.-1 Hydrogel formulation (A) +
25357 4.2% microbeads Hydrogel formulation (A) + 23828 8.3%
microbeads Hydrogel formulation (A) 22022
[0103] Viscoelastic properties of microbeads added to hydrogel
formulation embodiment tested via oscillatory rheometery at angular
frequency of 10 rads per second and 37.degree. C. are shown below
in Table 10 and in FIG. 8. As shown, the addition of microbeads
increases the viscoelastic performance of the hydrogel
formulation.
TABLE-US-00010 TABLE 10 Viscoelastic Properties with Microbeads G'
G'' Complex viscosity Tan Agent (Storage Modulus Pa) (Loss Modulus
Pa) (mPa s) (delta) Hydrogel formulation (A) + 8559 1596 870493
0.18 4.2% microbeads Hydrogel formulation (A) + 6683 1248 679911
0.18 8.3% microbeads Hydrogel formulation (A) 7560 1347 768857
0.18
[0104] In some embodiments, the use of microbeads to modify
viscoelastic characteristics can be employed within the hydrogels
disclosed herein to augment the composition (e.g., to use less
polymer material and provide the additional benefit of addition of
pharmaceutically active components for example, but not to limited
to, anticoagulation and antibacterial agents).
[0105] The ninth characteristic analyzed was the degree of mucosal
lift post injection within the submucosal space in a porcine
ex-vivo rectum. An important experimental result may be one where
the intestinal mucosal lift is maintained at 90% of the original
(immediately post-injection) height over 60 minutes using the
hydrogel formulation. Clinically, this can result in a hydrogel
formulation that provides a durable submucosal cushion, providing
increased protection and safety. In addition, upon incision of the
mucosa, the formulation can advantageously not leak out from the
submucosal space to maintain the mucosal lift and safety.
[0106] To analyze the mucosal lift, a 5.times.5 cm section of fresh
porcine rectum was placed on a temperature controlled heating pad
set at 37.degree. C. The tissue was allowed to equilibrate to
37.degree. C. and temperature was verified with the use of an
infrared thermometer (Etekcity Lasergrip.TM. 800). Upon the tissue
reaching steady state of 37.degree. C., 3 cc of the agent was
injected into the submucosal space. Two parameters were measured
over 1 hour: (1) dome height without incision--in millimeters; and
(2) dome height with incision--in millimeters. Normal saline
(Baxter, Deerfield, Ill.) and Eleview.TM. (Aries Pharmaceuticals,
California, USA) were used as reference agents.
[0107] Results are shown in FIGS. 9 and 10. As shown, the hydrogel
formulation 901 exhibits a maintenance of the mucosal lift one hour
post injection and therefore minimal dissipation within
physiological parameters. In contrast, the saline 905, Eleview 903,
and Hespan were only 50% present or less after 1 hour.
[0108] The tenth parameter examined was the ex-vivo mucosal surface
area pigment marking after injection of the hydrogel formulation
into the submucosal space of porcine rectum. The evaluation of the
surface area that the pigment occupies provides a quantification of
accuracy of the marking agent. An important experimental result
would be one where the post injection surface area would be a close
to the original injection area which would correspond to as precise
and accurate over time. Clinically, this can result in a
formulation that provides a deposition of pigment into the
intestine submucosal space over time that allows for accurate
detection.
[0109] To analyze the marking, a 5.times.5 cm section of fresh
porcine rectum was placed on a grounding pad which itself was
placed on a temperature controlled heating pad set at 37.degree. C.
Upon the tissue reaching steady state 37.degree. C., 3 cc of agent
was injected into the submucosal space using a standard 18G
syringe. In this experiment Spot.TM. (GI Supply) was used as a
reference agent, which is the current most widely used state of the
art in marking agents. One parameter was measured over time--the
surface area change over time without incision--in
millimeters2/minute. The surface area change over one hour at
37.degree. C. The hydrogel formulation exhibited the lowest surface
area change followed by saline and spot (see FIG. 11).
Advantageously, the hydrogel formulation exhibits minimal surface
area change over one hour at physiological conditions compared to
the reference agents, indicating minimal dissipation and providing
a hydrogel formulation that is precise and accurate.
[0110] The eleventh parameter analyzed was the accuracy post
injection into porcine rectum in-vivo over time. A key experimental
result would be one where there was an accurate and consistent
pigment deposition 60 days after injection. Clinically, this can
result in a hydrogel formulation that will allow subsequent
examinations of the patient where identification of the injected
area is precise and accurate to the original injection site.
[0111] To test the accuracy, a chronic in-vivo study was performed
to evaluate hydrogel's durability and accuracy post-injection to
simulate that of a doctor injecting the formulation adjacent to
pathology. The porcine model was used as the distal rectum and
submucosa closely resembles that of human anatomy. The hydrogel
formulation was delivered using a standard endoscope (Olympus
GIF-190L) and endoscopic needle injector (Boston Scientific
Interject 25G). The hydrogel formulations was injected into the
distal rectum of pigs using standard endoscopic equipment. The pigs
were kept alive post-procedure for 60 days and then sacrificed. The
distal colon was removed and pigment area corresponding to the
injection site was measured. Saline and Spot were used as reference
agents.
[0112] The pigmented area of the disclosed hydrogel formulations
described herein (circles) versus Spot (squares) and Saline
(triangles), 60 days post-injection are shown in FIG. 12. As shown,
the hydrogel formulation is more accurate and precise 60 days post
injection compared to the reference agents. Saline disappeared
completely during follow-up. This indicates that the disclosed
formulation's dissipation profile allows for accurate and precise
deposition of pigment into the intestine.
[0113] The twelfth parameter analyzed was the electrical conduction
of the hydrogel formulation upon the application of electrosurgical
energy. The quantification of electrosurgical conduction produced
per unit time during electrosurgical tool contact was undertaken.
This can be important clinically, as electrosurgical tool use will
be a standard clinical event whilst using such formulations. Here,
the conductivity in tissue was measured to indicate clinical
relevance. An important experimental result would be one where
there is no excessive electrosurgical contact between the
submucosal area and the deeper muscle layer with the
electrosurgical tool. Preventing unnecessary transmission of
electrosurgical energy to the deeper intestinal wall can avert
immediate or delayed perforation. Clinically, this can result in a
hydrogel formulation that increases safety.
[0114] To analyze the electrical conduction, an ex-vivo tissue
analysis using 5.times.5 cm section of fresh porcine rectum placed
on a grounding pad, which itself was placed on a temperature
controlled heating pad set at 37.degree. C. The tissue was allowed
to equilibrate to 37.degree. C. and temperature was verified with
the use of an infrared thermometer (Etekcity Lasergrip 800). Using
a standard endoscopic electrosurgical generator (Olympus ESG-100)
connected to an Olympus Snaremaster electrocautery snare,
electrical energy was applied to the formulation(s). One parameter
was measured: the degree of electrical energy transference from the
submucosal space to the deeper intestinal wall. Saline was used as
a reference agent.
[0115] Transference of electrical energy was confined to the
submucosa for the hydrogel formulation compared to normal saline
(where transference of electrical energy transfers through the
muscle layer). Advantageously, using the hydrogel formulations
disclosed herein, the electrical energy from the electrosurgical
tool was focused within the submucosal space providing a safer
submucosal agent to use compared to saline where the electrical
energy transference to deeper muscle wall was pronounced.
Experimental Study 2
[0116] In a second experimental study, a plurality of hydrogel
formulation as described were produced with varying amounts of
carbomer or different types of pigment, and the effects on dome
height and coloring in vivo were examined The hydrogel formulation
included Carbomer 1.9-2.5%, Poloxamer 1%, Xanthan Gum 1%, Sterile
water 75% solution, buffer 25% solution and pigment. Pigments
included in the study were Methylene Blue 1% solution and FDandC#1
1% solution. The method of producing the hydrogel formulation
included mixing of the polymers and liquid for a minimum of 1 hour
at 100 rpm stirring speed. After mixing, the solution was filtered
and was then ready to use.
[0117] The objective of this study was to determine the performance
of a submucosal injection formulation of a plurality of hydrogels
of varying composition. The performance of the hydrogel
formulations was compared to that of a control (Eleview.TM.). The
study included a determination of mucosal dome height post
injection as well as an evaluation of device set-up time.
[0118] The total time for the hydrogel formulations (on average) to
set up for injection relative to the time for Eleview.TM. is shown
in Table 11 below. Set-up time was classified as the time taken to
remove the agent from its packaging and prime a standard
commercially available endoscopic injection needle device of 240 cm
and 25 gauge in diameter. As indicated, the hydrogel formulation
set up faster than the control (e.g., 3-5 times faster).
TABLE-US-00011 TABLE 11 Time to set up for injection Time (seconds)
Hydrogel formulation 24.5 Eleview .TM. 96
[0119] Additionally, FIGS. 13A-13O show photographs of the lift
associated with the various hydrogel formulations relative to the
control over time (at 0 minutes, 15 minutes, 30 minutes, 45
minutes, and 60 minutes). FIGS. 13A-13C show the elevation achieved
through the use of the hydrogel formulation (FIG. 13A) relative to
the Eleview.TM. control (FIGS. 13B and 13C) over time. As shown,
the Eleview.TM. resulted in no elevation at 60 minutes, in contrast
to the hydrogel formulation, which still showed significant lift.
FIGS. 13D-F show the elevation achieved with a hydrogel of varying
carbomer concentration relative to the control. As shown, the
hydrogel formulation with 2% carbomer (FIG. 13E) produced the most
pronounced dome, followed by the hydrogel formulation with 1.6%
carbomer (FIG. 13D). The Eleview.TM. control (FIG. 13F) again
showed little lift at 60 minutes. FIG. 13G-13I also show the
elevation achieved with a hydrogel of varying carbomer
concentration relative to the control. As shown, the hydrogel
formulation with 2% carbomer (FIG. 13G) produced the most
pronounced dome, followed by the hydrogel formulation with 1.9%
carbomer (FIG. 13I). The Eleview.TM. control (FIG. 13H) again
showed little lift at 60 minutes. FIGS. 13J-K all show that a
hydrogel formulation with 2.5% carbomer results in substantial lift
through 60 minutes. Finally, FIGS. 13M-13O show how different dyes
can affect the lift and/or coloring upon injection. The hydrogel
formulation with methylene blue (FIG. 13M) and the hydrogel
formulation with FDandC#1 (FIG. 13N) both resulted in lasting color
and lift at 60 minutes while the Eleview.TM. control (FIG. 13O) did
not.
[0120] The experimental results indicated that concentrations of
carbomer about 1.9%-2.5%, such as 2.0%, with or without dye produce
the best lift through 60 minutes (e.g., through the average time of
a submucosal lift procedure). Additionally, concentrations of 2.5%
or below can advantageously ensure that the hydrogel formulation
dissipates within 90 minutes or so, thereby enhancing safety of the
formulation. Further, controlled incision of the intestinal mucosa
as seen in this experiment demonstrates appropriate electrosurgical
conduction, which can be advantageous in removal of pathological
lesions e.g. colon polyps.
Experimental Study 3
[0121] In a third experimental study, the rheological properties of
a hydrogel comprising , the hydrogel includes poloxamer (5%),
carbomer (1.9-2.5%), xanthum gum (1%), sterile water (74%), pigment
(1%) and a buffer (25%) were compared to a constant (Eleview.TM.).
In particular, the difference in viscosities at 1 rad/s of force
(simulating stationary) relative to 10 rad/s of force (simulating
injection force) was analyzed. In order to make injection of the
formulation easy while still maintaining substantial viscosity upon
injection, it is advantageous for the viscosity of the hydrogel
formulation to be significantly lower upon the application of force
than the viscosity of the hydrogel formulation when stationary. The
results are shown in Table 12 below. As indicated, the hydrogel
formulation at 22.degree. C. and at 10 rad/s can have a viscosity
that is less than 50%, such as less than 30% of the viscosity at
22.degree. C. and at 1 rad/sec. Moreover, the hydrogel formulation
at 37.degree. C. and at 10 rad/s can have a viscosity that is less
than 30%, such as less than 20% of the viscosity at 37.degree. C.
and at 1 rad/sec. As shown, the difference between the viscosities
of the hydrogel formulation when stationary and during injection is
much higher than the difference between the viscosities of the
control (Eleview.TM.) when stationary versus injected. Further, as
shown below, the viscosity of the hydrogel formulation at
37.degree. C. can be less than 10 Pas, such as less than 5 Pas,
such as less than 4 Pas at shear rates of up to 10 rad/s. Further,
the viscosity of the hydrogel at 37.degree. C. can be greater than
0.2 Pas, such as greater than 0.3 Pas, such as greater than 0.5
Pas. These viscosities can advantageously ensure that the hydrogel
spreads evenly and dissipates timely while still providing adequate
lifting during the submucosal lift procedure.
TABLE-US-00012 TABLE 12 Rheological Properties Viscosity (Pa s)
22.degree. C. 37.degree. C. Agent 1 rad/s 10 rad/s 1 rad/s 10 rad/s
Hydrogel formulation 0.7983 0.3131 3.1367 0.5917 Eleview .TM.
0.0051 0.0048 0.0100 0.0036
Experimental Study 4
[0122] In a fourth experimental study, the effects of electron beam
sterilization on the hydrogel formulation were examined. The
formulation consisted of poloxamer (5%), carbomer (2.5%), xanthan
gum (1%), water by solution (50%), buffer (25%) and 1% methylene
blue (25%). That is, electron beam sterilization can be used to
ensure sterility before use of the hydrogel formulation for use in
the body. Such sterilization, however, can raise the temperature of
the hydrogel and result in altering the characteristics of the
hydrogel. In particular, the percentage height maintenance of the
hydrogel over time can be decreased as a result of electron beam
sterilization. It was determined that a total dosage of 20-30 kGy
of electron beam radiation (with 1-3 refrigeration cycles
therebetween to decrease the temperature of the gel) can
advantageously result in gels with a low dissipation rate at 45-60
minutes.
Conclusions
[0123] As used herein, the term "viscosity" refers to the
resistance of a liquid or semisolid against flow. The flow of
liquids or semisolids is described by viscosity, or, more
precisely, by shear viscosity .eta.. The shear viscosity of a fluid
expresses its resistance to shearing flows, where adjacent layers
move parallel to each other with different speeds. Common units of
measurement of viscosity are the pascal-second (Pas), the poise (P)
and "cP" centipoises. 1 poise (P) corresponds to 0.1 pascal-second
(Pas); 1 centipoise (cP) corresponds to 1 millipascal-second
(mPas).
[0124] As used herein, the term "non-toxic" refers to compounds
that are not harmful to the area coming in contact with the
compound. In some instances, the term may refer to compounds that
are not harmful or toxic to the body in general. In other
instances, the term refers to the compound being safe for use and
not harmful in the concentration and quantity being used at any one
time.
[0125] As used herein, the term "bio-compatible" refers to
compounds that are not harmful to tissue with which they come into
contact with. In some instances, the term refers to compounds or
agents that do not elicit an immune response from the tissue or
systems that it comes into contact with. In other instances, the
term refers also to the compound's metabolized products being not
harmful to the tissue and systems it comes into contact with.
[0126] As used herein an "aqueous fluid" (e.g., a solution,
suspension, etc.) is one which contains water, typically from 70
wt% to 99 wt % or more water. In addition, a co-solvent may be
added e.g., normal saline typically from 10 wt% to 90 wt %.
[0127] As used herein a hydrogel is a material (in anhydrous or
hydrated form) that contains polymers that form complex networks
upon reaction to external stimuli e.g. temperature and pH.
[0128] As used here, a "polymer" is a material that contains bonded
repeated subunits that are the same, also termed monomers. The
number of monomers that make up the polymer varies according to the
specifications, but in the hydrogel formulations described herein
can refer to up to 10,000 subunits. In the anhydrous form, the
polymers can make up to 99% of the total weight of the hydrogel.
Monomers may also be free monomers that make up the constituents of
the polymer. In the hydrated form polymers may make up 0.001% to
50% of the volume. If a polymer contains single repeated monomer,
it is known as a homopolymer. If a polymer has 2 repeated monomers
it is known as a co-polymer. A block co-polymer refers to that
co-polymer that contains 2 or more polymer chains of different
components. Triblock contains 3 polymer chains and so on. The
constituents of a block copolymer can be both made up of
homopolymers and co-polymers.
[0129] In some embodiments, the hydrogels described herein do not
include poly(propylene oxide). In some embodiments, the hydrogels
do not include poly(ethylene oxide). In some embodiments, the
hydrogel composition does not include an oily component.
[0130] When a feature or element is herein referred to as being
"on" another feature or element, it can be directly on the other
feature or element or intervening features and/or elements may also
be present. In contrast, when a feature or element is referred to
as being "directly on" another feature or element, there are no
intervening features or elements present. It will also be
understood that, when a feature or element is referred to as being
"connected", "attached" or "coupled" to another feature or element,
it can be directly connected, attached or coupled to the other
feature or element or intervening features or elements may be
present. In contrast, when a feature or element is referred to as
being "directly connected", "directly attached" or "directly
coupled" to another feature or element, there are no intervening
features or elements present. Although described or shown with
respect to one embodiment, the features and elements so described
or shown can apply to other embodiments. It will also be
appreciated by those of skill in the art that references to a
structure or feature that is disposed "adjacent" another feature
may have portions that overlap or underlie the adjacent
feature.
[0131] Terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
the invention. For example, as used herein, the singular forms "a",
"an" and "the" are intended to include the plural forms as well,
unless the context clearly indicates otherwise. It will be further
understood that the terms "comprises" and/or "comprising," when
used in this specification, specify the presence of stated
features, steps, operations, elements, and/or components, but do
not preclude the presence or addition of one or more other
features, steps, operations, elements, components, and/or groups
thereof. As used herein, the term "and/or" includes any and all
combinations of one or more of the associated listed items and may
be abbreviated as "/".
[0132] Spatially relative terms, such as "under", "below", "lower",
"over", "upper" and the like, may be used herein for ease of
description to describe one element or feature's relationship to
another element(s) or feature(s) as illustrated in the figures. It
will be understood that the spatially relative terms are intended
to encompass different orientations of the device in use or
operation in addition to the orientation depicted in the figures.
For example, if a device in the figures is inverted, elements
described as "under" or "beneath" other elements or features would
then be oriented "over" the other elements or features. Thus, the
exemplary term "under" can encompass both an orientation of over
and under. The device may be otherwise oriented (rotated 90 degrees
or at other orientations) and the spatially relative descriptors
used herein interpreted accordingly. Similarly, the terms
"upwardly", "downwardly", "vertical", "horizontal" and the like are
used herein for the purpose of explanation only unless specifically
indicated otherwise.
[0133] Although the terms "first" and "second" may be used herein
to describe various features/elements (including steps), these
features/elements should not be limited by these terms, unless the
context indicates otherwise. These terms may be used to distinguish
one feature/element from another feature/element. Thus, a first
feature/element discussed below could be termed a second
feature/element, and similarly, a second feature/element discussed
below could be termed a first feature/element without departing
from the teachings of the present invention.
[0134] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising" means various
components can be co-jointly employed in the methods and articles
(e.g., compositions and apparatuses including device and methods).
For example, the term "comprising" will be understood to imply the
inclusion of any stated elements or steps but not the exclusion of
any other elements or steps.
[0135] As used herein in the specification and claims, including as
used in the examples and unless otherwise expressly specified, all
numbers may be read as if prefaced by the word "about" or
"approximately," even if the term does not expressly appear. The
phrase "about" or "approximately" may be used when describing
magnitude and/or position to indicate that the value and/or
position described is within a reasonable expected range of values
and/or positions. For example, a numeric value may have a value
that is +/-0.1% of the stated value (or range of values), +/-1% of
the stated value (or range of values), +/-2% of the stated value
(or range of values), +/-5% of the stated value (or range of
values), +/-10% of the stated value (or range of values), etc. Any
numerical range recited herein is intended to include all
sub-ranges subsumed therein.
[0136] Although various illustrative embodiments are described
above, any of a number of changes may be made to various
embodiments without departing from the scope of the invention as
described by the claims. For example, the order in which various
described method steps are performed may often be changed in
alternative embodiments, and in other alternative embodiments one
or more method steps may be skipped altogether. Optional features
of various device and system embodiments may be included in some
embodiments and not in others. Therefore, the foregoing description
is provided primarily for exemplary purposes and should not be
interpreted to limit the scope of the invention as it is set forth
in the claims.
[0137] The examples and illustrations included herein show, by way
of illustration and not of limitation, specific embodiments in
which the subject matter may be practiced. As mentioned, other
embodiments may be utilized and derived there from, such that
structural and logical substitutions and changes may be made
without departing from the scope of this disclosure. Such
embodiments of the inventive subject matter may be referred to
herein individually or collectively by the term "invention" merely
for convenience and without intending to voluntarily limit the
scope of this application to any single invention or inventive
concept, if more than one is, in fact, disclosed. Thus, although
specific embodiments have been illustrated and described herein,
any arrangement calculated to achieve the same purpose may be
substituted for the specific embodiments shown. This disclosure is
intended to cover any and all adaptations or variations of various
embodiments. Combinations of the above embodiments, and other
embodiments not specifically described herein, will be apparent to
those of skill in the art upon reviewing the above description.
* * * * *