U.S. patent application number 12/554381 was filed with the patent office on 2009-12-31 for medical composition for protuberance of epithelium.
This patent application is currently assigned to SEIKAGAKU CORPORATION. Invention is credited to Shin-ichi ISHIKAWA, Junichi ONAYA.
Application Number | 20090325899 12/554381 |
Document ID | / |
Family ID | 19153814 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090325899 |
Kind Code |
A1 |
ISHIKAWA; Shin-ichi ; et
al. |
December 31, 2009 |
MEDICAL COMPOSITION FOR PROTUBERANCE OF EPITHELIUM
Abstract
A medical composition for protuberance of epithelium, which
comprises a solution comprising a polysaccharide or a medically
acceptable salt thereof, wherein the solution has a viscosity of:
(1) from 50 to 500 mPas at a shear rate of from 7.7 to 10.0
s.sup.-1; (2) from 45 to 300 mPas at a shear rate of from 19.2 to
20.0 s.sup.-1; and (3) from 40 to 200 mPas at a shear rate of from
38.3 to s.sup.-1, when measured using a rotational viscometer at
25.degree. C., and a syringe filled with the medical
composition.
Inventors: |
ISHIKAWA; Shin-ichi;
(Suginami-ku, JP) ; ONAYA; Junichi;
(Higashimurayama-shi, JP) |
Correspondence
Address: |
SUGHRUE-265550
2100 PENNSYLVANIA AVE. NW
WASHINGTON
DC
20037-3213
US
|
Assignee: |
SEIKAGAKU CORPORATION
Chiyoda-ku
JP
|
Family ID: |
19153814 |
Appl. No.: |
12/554381 |
Filed: |
September 4, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11324407 |
Jan 4, 2006 |
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12554381 |
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10286822 |
Nov 4, 2002 |
7008626 |
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11324407 |
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Current U.S.
Class: |
514/54 |
Current CPC
Class: |
A61K 31/728 20130101;
A61K 31/726 20130101 |
Class at
Publication: |
514/54 |
International
Class: |
A61K 31/728 20060101
A61K031/728 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 5, 2001 |
JP |
2001-339471 |
Claims
1-16. (canceled)
17. A method for resecting epithelium, which comprises:
administering an effective amount of a medical composition to under
epithelium to thereby obtain protuberance of the epithelium; and
resecting the protuberance, wherein the medical composition
comprises a solution comprising sodium hyaluronate having a weight
average molecular weight of from 880,000 to 920,000 and its
concentration in the solution is 0.4% (w/v).
18. The method according to claim 17, wherein the epithelium is
mucosa.
19. The method according to claim 18, wherein the mucosa is
digestive organ mucosa.
20. The method according to claim 17, which is used for a mucosal
resection.
21. The method according to claim 17, wherein the composition is
administered using a syringe.
Description
BACKGROUND OF THE PRESENT INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a medical composition for
protuberance of epithelium, which comprises a solution comprising a
polysaccharide or a salt thereof, wherein the solution has
predetermined properties. Also, the present invention relates to a
syringe filled with the medical composition.
[0003] 2. Brief Description of the Background Art
[0004] When it is necessary to apply a medical treatment to
epithelium, e.g., when it is necessary to excise epithelium, the
treatment can sometimes be facilitated by distending (elevating)
the epithelium.
[0005] For example, endoscopic mucosal resection (hereinafter also
referred to as "EMR") is a method in which mucosa, such as
digestive tracts, changed into a morbid state is excised by an
operation using an endoscope without ventrotomy, which is carried
out by excising the region of mucosa changed into a morbid state by
hooking the region with a wire loop attached to the tip of the
endoscope. In order to improve efficiency, workability and safety
of the operation, attempts have been made to develop a method for
distending (elevating) a mucosa region changed into a morbid state
by injecting a high molecular polymer solution into a lower layer
of the mucosa region changed into a morbid state.
[0006] Gastrointestinal Endoscopy, 50(2), pp. 251-256 (1999)
discloses that 1.0% sodium hyaluronate solution was used for
elevation of mucosa in EMR, and discloses that it was administered
using a disposable syringe.
[0007] Also, the same reference discloses that "a hypertonic saline
and epinephrine" and "a hypertonic saline with epinephrine and 50%
glucose" have been conventionally used for elevation of mucosa in
EMR.
[0008] Furthermore, Gastrointestinal Endoscopy, 50(5), pp. 701-704
(1999) discloses that a 0.5% sodium hyaluronate solution containing
a small amount of indigocarmine dye was used for elevation of
mucosa in EMR, and that it was administered using a 5 ml capacity
syringe.
[0009] Although EMR is an operation using an endoscope, a part of
vital tissues must be removed and, when burden to patients is taken
into consideration, it is preferable carry out the operation as
quickly and securely as possible. Thus, great concern has been
directed toward the development of a composition for quickly and
securely carrying out medical treatments of epithelium, including
the EMR.
SUMMARY OF THE INVENTION
[0010] An object of the present invention is to provide a
composition for more quickly and securely carrying out medical
treatments of epithelium, more particularly, a composition which
can quickly carry out injection of a solution in treatment of
epithelium, can keep high protuberance (elevation) of epithelium
for a certain period of time, can exclude the necessity for
additionally injecting a solution during the treatment of
epithelium as small as possible, and can improve workability in
treatment of epithelium.
[0011] Furthermore, an object of the present invention is to
provide a syringe which is quickly used for the protuberance
(elevation) of epithelium in treatment of epithelium.
[0012] These and other objects of the present invention have been
accomplished by a medical composition for protuberance (elevation)
of epithelium, which comprises a solution comprising a
polysaccharide or a medically acceptable salt thereof, wherein the
solution has a viscosity of:
(1) from 50 to 500 mPas at a shear rate of from 7.7 to 10.0
s.sup.-1; (2) from 45 to 300 mPas at a shear rate of from 19.2 to
20.0 s.sup.-1; and (3) from 40 to 200 mPas at a shear rate of from
38.3 to 40.0 s.sup.-1,
[0013] when measured using a rotational viscometer at 25.degree. C.
(hereinafter referred to as "composition of the present
invention").
[0014] Furthermore, these and other objects of the present
invention have been accomplished by a syringe filled with the
composition of the present invention (hereinafter referred to as
"syringe of the present invention").
[0015] Moreover, these and other objects of the present invention
have been accomplished by a method for resecting epithelium, which
comprises:
[0016] administering an effective amount of the medical composition
to under epithelium to thereby obtain protuberance of the
epithelium; and
[0017] resecting the protuberance.
DETAILED DESCRIPTION OF THE INVENTION
[0018] As a result of intensive studies carried out in order to
solve the above problems, the present inventors have found that
when a solution having specified properties is used, the solution
can be injected easily even through a thin catheter and needle and
also high protuberance of epithelium can be kept for a certain
period of time. Thus, the present invention has been completed.
[0019] It is preferable for the composition of the present
invention that, in a syringe having a catheter needle and a piston
which is filled with the solution, a force required for discharging
the solution from the tip of the catheter needle by pushing the
piston at a constant rate of 1 mm/second and at 25.degree. C.
is:
(1) 6.0 kgf or less when the catheter needle has a catheter length
of 1,650 mm and a needle diameter of 21 G (gauge); and (2) 10.0 kgf
or less when the catheter needle has a catheter length of 2,300 mm
and a needle diameter of 25 G (gauge).
[0020] Furthermore, it is preferable in the composition of the
present invention that, when 0.5 ml of the solution is injected
under mucosa in the vicinity of a greater curvature pyloric portion
of stomach of a rabbit from its gastric serosa side using an
injection needle having a needle diameter of 27 G and subsequently
allowed to stand for 30 minutes to obtain protuberance of the
mucosa, and then a region comprising the protuberance is quickly
frozen and vertically incised from the apex of the protuberance,
the protuberance in the vertically incised section has a height of
5.0 mm or more from a mucosa surface of a region to which the
solution is not injected.
[0021] The polysaccharide used in the composition of the present
invention is preferably a glycosaminoglycan, and the
glycosaminoglycan is preferably hyaluronic acid.
[0022] Also, when hyaluronic acid is used as the glycosaminoglycan,
its weight average molecular weight (hereinafter referred to as
"Mw") is preferably from 600,000 to 3,900,000, more preferably from
700,000 to 3,000,000, and most preferably from 700,000 to 1,200,000
or from 1,900,000 to 3,000,000.
[0023] It is also preferable that the composition of the present
invention further comprises chondroitin sulfate or a medically
acceptable salt thereof. In this case, the ratio of the "hyaluronic
acid or medically acceptable salt thereof" to the "chondroitin
sulfate or medically acceptable salt thereof" is preferably from
1/10 to 1/20 (w/w (weight/weight)).
[0024] The epithelium having protuberance obtained by the
composition of the present invention is preferably mucosa, and more
preferably digestive organ mucosa. Also, it is preferable to use
the composition of the present invention for a mucosal
resection.
<1> Composition of the Present Invention
[0025] The composition of the present invention is a medical
composition for protuberance of epithelium, which comprises a
solution comprising a polysaccharide or a medically acceptable salt
thereof, wherein the solution has a specific viscosity at each
shear rate shown in Table 1 below, when measured using a rotational
viscometer at 25.degree. C.
TABLE-US-00001 TABLE 1 Shear rate (s.sup.-1) Viscosity (mPa s) 7.7
to 10.0 50 to 500 19.2 to 20.0 45 to 300 38.3 to 40.0 40 to 200
(1) Polysaccharide or a Medically Acceptable Salt Thereof.
[0026] The polysaccharide used in the composition of the present
invention is not particularly limited, so long as it is suitable
for medical use, and various polysaccharides can be used but a
glycosaminoglycan is particularly preferable. Examples of the
glycosaminoglycan include hyaluronic acid, chondroitin sulfate,
keratan sulfate, heparin and heparan sulfate. Among these,
hyaluronic acid is more preferred.
[0027] Also, examples of the medically acceptable salt of
polysaccharide include medically acceptable salts selected from
salts with inorganic bases such as alkali metal salts (e.g., sodium
salts, lithium salts and potassium salts), alkaline earth metal
salts (e.g., calcium salts and magnesium salts) and ammonium salt,
and salts with organic bases such as diethanolamine salts,
cyclohexylamine salts and amino acid salts. Among these, alkali
metal salts are preferable, and sodium salts are more
preferable.
[0028] The present invention is specifically described with
reference to the case in which hyaluronic acid is used as the
polysaccharide.
[0029] The origin of hyaluronic acid or a medically acceptable salt
thereof used in this case is not particularly limited, and, e.g.,
those which are separated and purified from chicken crest,
umbilical cords or hyaluronic acid-producing microorganisms can be
used. Particularly preferred examples are those which are highly
purified and have substantially no substances whose contamination
is not allowed as a medicament. As the medically acceptable salt of
hyaluronic acid, the salts described above can be used, and sodium
hyaluronate is more preferable.
[0030] The Mw of hyaluronic acid or a medically acceptable salt
thereof used in the present invention is not particularly limited,
but is preferably shown in Table 2 below. The higher the No. in
Table 2 is, the more preferable the range is.
TABLE-US-00002 TABLE 2 No. Mw 1 600,000 to 3,900,000 2 700,000 to
3,000,000 3 700,000 to 1,200,000 or 1,900,000 to 3,000,000 4
800,000 to 1,000,000 or 1,900,000 to 2,500,000 5 850,000 to 950,000
or 2,000,000 to 2,400,000 6 880,000 to 920,000 or 2,100,000 to
2,300,000 7 about 900,000 or about 2,200,000
[0031] Also, the Mw of hyaluronic acid or a medically acceptable
salt thereof used in the present invention can be calculated based
on the equation of Laurent et al. (Biochim. Biophys. Acta, 42, 476
(1960)) by measuring a limiting viscosity in accordance with The
Japanese Pharmacopoeia, Thirteenth Edition, General Tests,
"Viscosity Determination" (1996).
[0032] Additionally, the preferable relationship between the
limiting viscosity of hyaluronic acid or a medically acceptable
salt thereof and the Mw is shown in Table 3 below.
TABLE-US-00003 TABLE 3 No. Mw Limiting viscosity (dl/g) 1 600,000
to 3,900,000 11.5 to 54.5 2 700,000 to 3,000,000 13.0 to 44.0 3
700,000 to 1,200,000 13.0 to 20.0 1,900,000 to 3,000,000 30.0 to
44.0 4 800,000 to 1,000,000 14.5 to 17.0 1,900,000 to 2,500,000
30.0 to 38.0 5 850,000 to 950,000 15.0 to 16.5 2,000,000 to
2,400,000 31.5 to 36.5 6 880,000 to 920,000 15.5 to 16.0 2,100,000
to 2,300,000 33.0 to 35.5 7 about 900,000 about 16.0 about
2,200,000 about 34.0
[0033] Preferably, the composition of the present invention further
comprises chondroitin sulfate or a medically acceptable salt
thereof, in addition to hyaluronic acid or a medically acceptable
salt thereof.
[0034] The origin of chondroitin sulfate or a medically acceptable
salt thereof used in this case is not particularly limited, and,
e.g., those which are separated and purified from cartilage of
fishes (e.g., sharks) and mammals (e.g., whales and cattle) can be
used. Particularly preferred examples are those which contain
substantially no substances whose contamination is not allowed as a
medicament. As the medically acceptable salt of chondroitin
sulfate, the salts described above can be used, and sodium
chondroitin sulfate is more preferable.
[0035] The Mw of chondroitin sulfate or a medically acceptable salt
thereof used herein is generally from several thousands to about
50,000, preferably from about 10,000 to 40,000, and more preferably
from about 20,000 to 30,000.
[0036] Particularly, sodium chondroitin sulfate having the
following properties (1) and (2) is exceedingly preferable:
(1) the nitrogen content when a dried sample is determined is from
2.5 to 3.8%; (2) the sulfur content when a dried sample is
determined is from 5.5 to 7.5%.
[0037] Furthermore, the sodium chondroitin sulfate having the
following properties (3) to (9) is more preferable:
(3) when 1.0 g of the sodium chondroitin sulfate is dissolved in
100 ml of water, the solution is colorless to slightly yellow
transparent; (4) the chloride content is 0.142% or less; (5) the
sulfate content is 0.24% or less; (6) the heavy metal content is 20
ppm or less; (7) the arsenic content is 2 ppm or less; (8) the
drying loss is 10.0% or less (1 g, 105.degree. C., 4 hours); (9)
the ignition residue is from 23.0 to 31.0% (1 g, after drying).
[0038] Also, the properties (1) to (9) can be measured by the
general tests described in A Guide for The Japanese Pharmacopoeia,
Thirteenth Edition (published by Hirokawa Shoten) and the methods
described in The Japanese Medical Codex (1997).
[0039] According to the composition of the present invention
further comprising chondroitin sulfate or a medically acceptable
salt thereof, in addition to hyaluronic acid or a medically
acceptable salt thereof, the ratio of the "hyaluronic acid or
medically acceptable salt thereof" to the "chondroitin sulfate or
medically acceptable salt thereof" is preferably from 1/10 to 1/20
(w/w).
[0040] A solution comprising the polysaccharide or a medically
acceptable salt thereof can be used as the solution comprising the
composition of the present invention. The solution can be prepared
by dissolving the polysaccharide or a medically acceptable salt
thereof in an appropriate medically acceptable solvent. A kind of
the solvent is not particularly limited, and sterilized distilled
water or physiological salt solution can be used.
[0041] Among the solutions of polysaccharide or a medically
acceptable salt thereof, a solution having the property shown in
Table 1 above is used as the composition of the present
invention.
[0042] As the rotational viscometer, a commercially available
product can be used, and the shear rate can be adjusted by
appropriately setting and selecting the rotation speed and type and
size of the rotor (rotating device). Specific type and size of the
rotor are not particularly limited, so long as they are generally
used, and, e.g., a cone spindle type having "an angle of 1.degree.
34' and a radius of 24 mm" or "an angle of 3.degree. and a radius
of 14 mm" can be used. The most preferable example is referred to
Example described below.
[0043] Using such an instrument, a solution can be obtained used as
the composition of the present invention, by appropriately
adjusting a kind and an amount of the polysaccharide or a medically
acceptable salt thereof and the solvent in such a manner that the
solution shows each of the viscosity at each of the shear rate at
25.degree. C.
[0044] A concentration of the polysaccharide or a medically
acceptable salt thereof in the solution used as the composition of
the present invention is not limited, so long as it has the
property described in the above, and can be appropriately set in
response to the kind, Mw and combination of the polysaccharide or a
medically acceptable salt thereof. When two or more polysaccharides
or medically acceptable salts thereof are used, it may be
considered in the same manner on a solution in which they are
mixed.
[0045] Furthermore, preferably, the solution used as the
composition of the present invention further has the following
property.
[0046] In a syringe having a catheter needle and a piston which is
filled with the solution, a preferable range of a force required
for discharging the solution from the tip of the catheter needle by
pushing the piston at a constant rate of 1 mm/second at 25.degree.
C. is shown in Table 4 below. The higher the No. in Table 4 is, the
more preferable the range is.
TABLE-US-00004 TABLE 4 Force Catheter needle (1) Catheter needle
(2) Catheter length: 1,650 mm Catheter length: 2,300 mm No. Needle
diameter: 21 G Needle diameter: 25 G 1 6.0 kgf or less 10.0 kgf or
less 2 6.0 kgf or less 9.0 kgf or less 3 5.0 kgf or less 7.5 kgf or
less 4 5.0 kgf or less 7.0 kgf or less 5 4.0 kgf or less 7.0 kgf or
less
[0047] The property can be measured by filling a syringe equipped
with a catheter needle having the predetermined catheter length and
needle diameter with the solution, and measuring a force required
for discharging the solution from the tip of the catheter needle by
pushing the piston at a constant rate of 1 mm/second. The
measurement is carried out at 25.degree. C. An inner diameter of
the cylinder of the syringe (outer diameter of the piston under a
state of being kept inside the cylinder) is set to about 14 mm. The
most preferable example of the measuring method is referred to
Example described below.
[0048] Furthermore, preferably, the composition of the present
invention further has the following property.
[0049] When 0.5 ml of the solution is injected under mucosa in the
vicinity of a greater curvature pyloric portion of stomach of a
rabbit from its gastric serosa side using an injection needle
having a needle diameter of 27 G and subsequently allowed to stand
for 30 minutes to obtain protuberance of the mucosa, and then a
region comprising the protuberance is quickly frozen and vertically
incised from the apex of the protuberance, the protuberance in the
vertically incised section has an average height of 5.0 mm or more,
preferably 5.1 mm or more, and more preferably 5.2 mm or more, from
a mucosa surface of a region to which the solution is not
injected.
[0050] Since there is a possibility that an amount of the solution
leaked from the region where the needle is inserted slightly
differs depending on the needle diameter (thickness), the needle
diameter of the needle was specified to 27 G in specifying the
property in order to exclude influences caused thereby. Also, it is
preferable to use dry ice for the quick freezing.
[0051] After the quick freezing, the administered region is
vertically incised from the protuberance apex (vertical incision
against the mucosa surface to which the solution is not
administered). Next, using the mucosa surface in the section
appeared by the vertical incision, to which the solution is not
administered, as a standard, the height therefrom to the
protuberance apex of the mucosa (mucosa surface being the
protuberance apex) is measured. It is necessary to carry out a
series of these operations while the frozen state is maintained,
and since the measurement must be accurate and objective, it is
preferable to measure the height by photographing the section
appeared by the vertical incision and subjecting it to image
analysis.
[0052] The evaluation of the height is preferably carried out using
an average value based on plural tests. The tests are carried out,
for example, about 4 times.
[0053] The most preferable example of the measuring method is
referred to Example described below.
[0054] By using the solution comprising a polysaccharide or a
medically acceptable salt thereof, the composition of the present
invention which can perform easy solution injection and has good
ability to keep protuberance of epithelium can be obtained.
[0055] Preferable examples of the solution comprising a
polysaccharide or a medically acceptable salt thereof used in the
composition of the present invention include:
(a) from 0.35 to 0.44% (w/v (weight/volume)) of sodium hyaluronate
(Mw: from 700,000 to 1,200,000); (b) from 0.15 to 0.34% (w/v) of
sodium hyaluronate (Mw: from 1,900,000 to 3,000,000); and (c) a
combination of from 0.05 to 0.24% (w/v) of sodium hyaluronate (Mw:
from 1,900,000 to 3,000,000) with from 1.5 to 2.4% (w/v) of sodium
chondroitin sulfate (Mw: from to 30,000).
[0056] In the above solution (a), more preferable ranges are shown
in Table 5 below. The higher the No. in Table 5 is, the more
preferable the range is.
TABLE-US-00005 TABLE 5 Sodium hyaluronate No. Mw Concentration
(w/v) 1 800,000 to 1,000,000 0.35 to 0.44% 2 850,000 to 950,000
0.35 to 0.44% 3 850,000 to 950,000 0.38 to 0.42% 4 880,000 to
920,000 0.38 to 0.42% 5 880,000 to 920,000 0.4% 6 about 900,000
0.4%
[0057] In the above solution (b), more preferable ranges are shown
in Table 6 below. The higher the No. in Table 6 is, the more
preferable the range is.
TABLE-US-00006 TABLE 6 Sodium hyaluronate No. Mw Concentration
(w/v) 1 1,900,000 to 2,500,000 0.15 to 0.34% 2 2,000,000 to
2,400,000 0.15 to 0.34% 3 2,100,000 to 2,300,000 0.15 to 0.34% 4
2,100,000 to 2,300,000 0.18 to 0.32% 5 2,150,000 to 2,250,000 0.18
to 0.32% 6 2,150,000 to 2,250,000 0.2% or 0.3% 7 about 2,200,000
0.2% or 0.3%
[0058] In the above solution (c), more preferable combinations and
ranges are shown in Table 7 below. The higher the No. in Table 7
is, the more preferable the combination and range are.
TABLE-US-00007 TABLE 7 Sodium hyaluronate Sodium chondroitin
sulfate No. Mw Conc. (w/v) Mw Conc. (w/v) 1 1,900,000 to 0.05 to
0.24% 20,000 to 1.5 to 2.4% 2,500,000 30,000 2 2,000,000 to 0.05 to
0.24% 20,000 to 1.5 to 2.4% 2,400,000 30,000 3 2,100,000 to 0.05 to
0.24% 20,000 to 1.5 to 2.4% 2,300,000 30,000 4 2,100,000 to 0.08 to
0.22% 20,000 to 1.5 to 2.4% 2,300,000 30,000 5 2,150,000 to 0.08 to
0.22% 20,000 to 1.5 to 2.4% 2,250,000 30,000 6 2,150,000 to 0.08 to
0.22% 20,000 to 1.8 to 2.2% 2,250,000 30,000 7 2,150,000 to 0.1% or
0.2% 20,000 to 1.8 to 2.2% 2,250,000 30,000 8 2,150,000 to 0.1% or
0.2% 20,000 to 2.0% 2,250,000 30,000 9 about 0.1% or 0.2% 20,000 to
2.0% 2,200,000 30,000
[0059] These are merely illustrations, and other examples can be
employed as solutions used in the composition of the present
invention, so long as they have the properties described in the
above.
[0060] Also, the concentration of endotoxin in the composition of
the present invention is preferably 0.25 EU/ml or less. The
endotoxin concentration can be measured using an endotoxin
measuring method well known and conventionally used by those
skilled in the art, but the Limulus test method which uses
horseshoe crab amoebocyte lysate components is preferable. Also,
the EU (endotoxin unit) can be measured and calculated in
accordance with the Japanese Industrial Standard, Biochemical
Reagent Provisions (JIS K8008). Also, the iron content is
preferably 20 ppm or less.
[0061] Also, the composition of the present invention preferably
has a pH of from 3 to 10, more preferably from 4 to 10, still more
preferably from 5 to 9, most preferably from 6 to 8, and far most
preferably 6.8 to 7.8.
[0062] Moreover, the composition of the present invention
preferably has an osmotic pressure ratio (a ratio to physiological
saline) of from 0.7 to 1.4, more preferably from 0.8 to 1.3, and
most preferably from 0.9 to 1.2.
[0063] Furthermore, other medicinally active components and
components generally used in medicaments such as generally used
stabilizers, emulsifiers, osmotic pressure controlling agents,
buffer agents, tonicity agents, preservatives, soothing agents,
coloring agents, fillers, binders, lubricants and disintegrating
agents can be contained in the composition of the present
invention, so long as they do not have bad influences on the
polysaccharide or a medically acceptable salt thereof contained in
the composition of the present invention, do not have influences on
the effects of the present invention and have the properties as the
composition of the present invention.
[0064] The epithelium distended by the composition of the present
invention is not limited, so long as it is an epithelium whose
protuberance is desired, and examples include skin and mucosa.
Particularly, mucosa is preferable.
[0065] Mucosa includes digestive organ mucosa (e.g., oral mucosa
and gastrointestinal mucosa), respiratory organ mucosa (e.g., nasal
septum mucosa) and urogenital mucosa (e.g., bladder mucosa, vaginal
mucosa and uterine mucosa). Among these, digestive organ mucosa is
preferable.
[0066] Among the digestive organ mucosa, gastrointestinal mucosa is
preferable. Examples of the gastrointestinal mucosa include
esophageal mucosa, gastric mucosa, duodenal mucosa and large
intestine mucosa.
[0067] The composition of the present invention is preferably used
in mucosal resection. Regarding the mucosal resection, various
operation methods are known in response to the regions where the
mucosal resection is carried out and the tools and methods to be
employed. Specifically, endoscopic mucosal resection (EMR), mucosal
resection under a laparoscope, mucosal resection under a
hysteroscope, transurethral bladder tumor resection and mucosal
resection using a laser can be exemplified, and the composition of
the present invention can be used in any one of these mucosal
resections. Also, it is particularly preferable that the
composition of the present invention is used in endoscopic mucosal
resection (EMR) among these.
[0068] The composition of the present invention can be used by
administering it under an epithelium region where protuberance of
epithelium is required. When the composition of the present
invention is administered under an epithelium, the administered
composition of the present invention retains between the epithelium
and muscle layer, and the epithelium is distended thereby. In order
to prevent leaking of the administered composition of the present
invention, the composition of the present invention is preferably
administered by injection. Since medical treatment of epithelium
becomes easy by distending the epithelium, epithelium treatment can
be carried out more quickly and accurately.
[0069] A dose of the composition of the present invention is
appropriately selected, depending on the object for treating
epithelium, area of the epithelium to be treated and the
administration method, without limitation, but roughly, 5 to 100 ml
can be exemplified when used in human EMR.
[0070] Also, when the composition of the present invention is
administered by injection, it can be used by filling it in a
syringe at the clinical field, but the filling labor and risk of
causing contamination at the field can be reduced by the use of the
following syringe of the present invention.
<2> Syringe of the Present Invention
[0071] The syringe of the present invention is a drug-filled
syringe in which the composition of the present invention is filled
in advance. According to the syringe of the present invention, the
composition of the present invention filled in the syringe is
sealed with a piston, a plunger, a stopper or a cap, so that it can
be distributed under conditions of being filled with the
composition of the present invention. The syringe of the present
invention can be produced by filling the composition of the present
invention in a syringe.
[0072] The composition of the present invention filled in the
syringe of the present invention is described above.
[0073] A material, shape and size of the syringe filled with the
composition of the present invention are not particularly limited,
and those which are already known can be employed.
[0074] Furthermore, the method for filling the composition of the
present invention in the syringe is also not particularly limited,
and a known method can be employed.
[0075] When the syringe of the present invention is used, the labor
for filling the composition of the present invention in a syringe
and risk of causing contamination at the clinical field can be
reduced.
[0076] The composition of the present invention can be injected
quickly and easily as a solution even through thin catheter and
needle and can keep a high protuberance of epithelium during its
treatment. Thus, the composition of the present invention
contributes to easier treatment of the epithelium as a vital tissue
and to the shortening of the treating period. Also, since a
necessity for additionally injecting a solution during the
treatment can be reduced, the treatment can be carried out more
safely and accurately. Accordingly, the composition of the present
invention leads to the alleviation of burden on a patient who is
subjected to a treatment of epithelium and therefore is markedly
useful.
[0077] Furthermore, the syringe of the present invention is
markedly useful, because it is already filled with the composition
of the present invention, so that labor for the filling and risk of
causing contamination at the clinical field can be reduced.
[0078] The present invention is described in more detail based on
Example; however, the present invention is not limited thereto.
Example
1. Substances to be Tested
(1) Sodium Hyaluronate
[0079] The following sodium hyaluronate samples were used as the
medically acceptable salt of hyaluronic acid:
(a) Mw: 900,000, limiting viscosity: 15.9 dl/g (hereinafter
referred to as "HA90"); (b) Mw: 2,200,000, limiting viscosity: 34.0
dl/g (hereinafter referred to as "HA220"); (c) a commercially
available sodium hyaluronate intraarticular injection (trade name:
Suvenyl.RTM., available from Chugai Pharmaceutical, average
molecular weight: 1,900,000 to 2,500,000) (hereinafter referred to
as "HA-S"); and (d) a commercially available sodium hyaluronate
agent (trade name: Healon.RTM., available from Pharmacia, average
molecular weight: 1,900,000 to 3,900,000) (hereinafter referred to
as "HA-H").
(2) Sodium Chondroitin Sulfate
[0080] As the medically acceptable salt of chondroitin sulfate,
sodium chondroitin sulfate (hereinafter referred to as "CS")
prepared by extracting a shark cartilage by treating it with a
protease in the usual way, subjecting the extract to a
deproteinization using a protease after removing fat and solid
contents and then purifying it by an alcohol precipitation method
was used.
[0081] The Mw of the CS was 30,000, and its dried product (powder)
showed the following properties:
(1) the nitrogen content: 3.40%; (2) the sulfur content: 6.82%; (3)
color of liquid when 1.0 g of the compound is dissolved in 100 ml
of water: colorless to slightly yellow transparent; (4) the
chloride content: 0.142% or less; (5) the sulfate content: 0.24% or
less; (6) the heavy metal content: 20 ppm or less; (7) the arsenic
content: 2 ppm or less; (8) the drying loss: 5.67% (1 g,
105.degree. C., 4 hours); and (9) the ignition residue: 26.3% (1 g,
after drying).
2. Preparation of Various Solutions and Viscosity
[0082] Solutions were prepared by dissolving the HA90, HA220, HA-S,
HA-H and CS in physiological saline to give the following
composition concentration (% (w/v)). Also, the viscosity (mPas) of
each of these solutions at the following shear rate was measured at
25.degree. C. using an RE80L type rotational viscometer and a cone
spindle type rotor (angle: 1.degree. 34'; radius: 24 mm)
(manufactured by Toki Sangyo Co., Ltd.). The results are shown in
Tables 8 and 9 below. In this case, * shows that it is an example
of the composition of the present invention, and "ND" means that
the measurement was not carried out.
TABLE-US-00008 TABLE 8 Shear rate 7.7 s.sup.-1 19.2 s.sup.-1 38.3
s.sup.-1 (1) Physiological saline ND ND ND (2) 0.1% HA220 ND 18.7
16.1 (3) 0.2% HA220 * 134.7 93.7 ND (4) 0.3% HA220 * ND ND ND (5)
0.4% HA90 * 52.2 50.6 47.6 (6) 0.5% HA90 94.3 88.9 ND (7) 0.2% HA-S
* ND ND ND (8) 0.25% HA-S * ND ND ND (9) 0.3% HA-S * ND ND ND (10)
0.2% HA-H * ND ND ND (11) 0.25% HA-H * ND ND ND (12) 0.3% HA-H * ND
ND ND (13) 2.0% CS ND ND 7.4 (14) 3.0% CS ND 13.8 13.6 (15) 4.0% CS
ND 24.8 24.8 (16) 5.0% CS 41.1 40.7 40.7 (17) 2.0% CS + 0.05% HA220
22.2 20.2 19.0 (18) 2.0% CS + 0.1% HA220 * 58.8 49.2 41.8 (19) 2.0%
CS + 0.2% HA220 * ND ND ND (20) 3.0% CS + 0.05% HA220 36.9 34.4
32.3
TABLE-US-00009 TABLE 9 Shear rate 1.9 s.sup.-1 3.8 s.sup.-1 (19)
2.0% CS + 0.2% HA220 * 397.2 243.3
[0083] Also, the viscosity (mPas) of each of the following
solutions at the following shear rate was measured under the same
conditions, except that a cone spindle type rotor (angle:
3.degree.; radius: 14 mm) (manufactured by Toki Sangyo Co., Ltd.)
was used as the rotor. The results are shown in Table 10 below.
TABLE-US-00010 TABLE 10 Shear rate 8.0 s.sup.-1 20.0 s.sup.-1 40.0
s.sup.-1 (3) 0.2% HA220 * ND 94.9 68.1 (4) 0.3% HA220 * 323.8 205.1
137.1 (5) 0.4% HA90 * ND 61.1 57.6 (6) 0.5% HA90 ND 132.2 117.4 (7)
0.2% HA-S * ND 68.6 54.5 (8) 0.25% HA-S * 177.3 132.2 98.5 (9) 0.3%
HA-S * 306.2 215.3 152.3 (10) 0.2% HA-H * 163.6 109.6 77.5 (11)
0.25% HA-H * 280.8 175.2 117.2 (12) 0.3% HA-H * 465.9 274.6
177.1
[0084] It was found from the above results that (3) 0.2% HA220, (4)
0.3% HA220, (5) 0.4% HA90, (6) 0.5% HA90, (7) 0.2% HA-S, (8) 0.25%
HA-S, (9) 0.3% HA-S, (10) 0.2% HA-H, (11) 0.25% HA-H, (12) 0.3%
HA-H, (18) 2.0% CS+0.1% HA220 and (19) 2.0% CS+0.2% HA220 satisfied
the following conditions shown in Table 11, but the other solutions
did not satisfied them.
TABLE-US-00011 TABLE 11 Shear rate (s.sup.-1) Viscosity (mPa s) 7.7
to 10.0 50 to 500 19.2 to 20.0 45 to 300 38.3 to 40.0 40 to 200
[0085] Also, the measurement was not carried out regarding the
"ND", and the measurement was not carried out at the predetermined
shear rate particularly on (19) 2.0% CS+0.2% HA220, but whether or
not they satisfy the above conditions can be easily judged by those
skilled in the art when the results at other shear rate are
compared with the technical common knowledge in the technical
field.
[0086] When the endotoxin concentration in these solutions was
measured using Toxi Color (trade name; manufactured by Seikagaku
Corporation), it was 0.25 EU/ml or less in all of them. Also, the
iron content was 20 ppm or less in all of them.
[0087] Furthermore, the pH of these solutions was within the range
of from 6.8 to 7.8, and the osmotic pressure ratio (ratio to
physiological saline) was within the range of from 0.9 to 1.2.
3. Discharging Force from Needle
[0088] Also, a syringe (inner diameter of the cylinder: 14 mm)
equipped with the following catheter needle was filled with each of
these solutions, and a force required for discharging the solution
from the tip of a catheter needle when a piston of the syringe was
pushed at a constant rate of 1 mm/second was measured under a
condition of 25.degree. C. using a rheometer (trade name: FUDOH
Rheometer NRM-2020J Type, manufactured by Rheotech).
(1) Catheter length: 1,650 mm, needle diameter: 21 G (product name:
Disposable Needle NM NM-200L-0421, manufactured by Olympus;
hereinafter also referred to as "Catheter 1") (2) Catheter length:
2,300 mm, needle diameter: 25 G (product name: Disposable Needle NM
NM-200U-0625, manufactured by Olympus; hereinafter also referred to
as "Catheter 2")
[0089] The results obtained by calculating average values by
measuring 1 to 3 times for each sample are shown in Table 12 below
as "average value+standard deviation (kgf)". In this case, * shows
that it is an example of the composition of the present invention,
and "ND" means that the measurement was not carried out.
TABLE-US-00012 TABLE 12 Catheter 1 Catheter 2 (1) Physiological
saline 0.4 .+-. 0.05 0.7 .+-. 0.07 (2) 0.1% HA220 1.3 .+-. 0.04 2.4
.+-. 0.00 (3) 0.2% HA220 * 2.6 .+-. 0.06 4.3 .+-. 0.16 (4) 0.3%
HA220 * 3.8 .+-. 0.00 6.4 .+-. 0.00 (5) 0.4% HA90 * 4.5 .+-. 0.00
6.9 .+-. 0.29 (6) 0.5% HA90 6.5 .+-. 0.00 9.6 .+-. 0.58 (13) 2.0%
CS 1.9 .+-. 0.01 4.2 .+-. 0.07 (14) 3.0% CS 3.6 .+-. 0.13 7.5 .+-.
0.09 (15) 4.0% CS 6.3 .+-. 0.24 12.8 .+-. 0.30 (16) 5.0% CS 10.0
.+-. 0.30 19.2 .+-. 0.73 (17) 2.0% CS + 0.05% HA220 2.9 .+-. 0.10
6.0 .+-. 0.08 (18) 2.0% CS + 0.1% HA220 * 3.9 .+-. 0.08 7.1 .+-.
0.00 (19) 2.0% CS + 0.2% HA220 * 5.6 .+-. 0.13 9.6 .+-. 0.00 (20)
3.0% CS + 0.05% HA220 5.0 .+-. 0.07 9.8 .+-. 0.28
4. Action to Maintain Protuberance (Elevation) of Epithelium
[0090] Under inhalation anesthesia of isoflurane (manufactured by
Dainippon Pharmaceutical), 0.5 ml of the solution was administered
under the mucosa in the vicinity of a greater curvature pyloric
portion of stomach of a rabbit of female JW species having a body
weight of from to 3.43 kg, from the gastric serosa side using a
needle having a needle diameter of 27 G. After 30 minutes of
standing, the stomach was excised, and the administered region was
quickly frozen with dry ice and then vertically incised from the
protuberance apex on the administered region (vertical incision
against the mucosa surface to which the solution was not
administered). The section appeared by the vertical incision under
frozen state was photographed, and using the mucosa surface of the
region to which the solution was not administered as a standard,
the height therefrom to the protuberance apex of the mucosa (mucosa
surface being the protuberance apex) was measured using an image
analyzing software (Image pro Plus.TM., manufactured by Media
Cybernetics). The results are shown in Table 13 below as "average
value.+-.standard deviation (mm) (4 sites for 1 group)". In this
case, * shows that it is an example of the composition of the
present invention.
TABLE-US-00013 TABLE 13 (1) Physiological saline 3.8 .+-. 0.6 (2)
0.1% HA220 4.8 .+-. 1.0 (3) 0.2% HA220 * 5.1 .+-. 0.4 (4) 0.3%
HA220 * 5.0 .+-. 0.5 (5) 0.4% HA90 * 5.2 .+-. 0.4 (6) 0.5% HA90 5.0
.+-. 0.4 (13) 2.0% CS 4.2 .+-. 0.8 (14) 3.0% CS 4.4 .+-. 0.5 (15)
4.0% CS 5.0 .+-. 0.6 (16) 5.0% CS 4.8 .+-. 0.8 (17) 2.0% CS + 0.05%
HA220 4.7 .+-. 0.3 (18) 2.0% CS + 0.1% HA220 * 5.6 .+-. 1.0 (19)
2.0% CS + 0.2% HA220 * 5.3 .+-. 0.5 (20) 3.0% CS + 0.05% HA220 4.9
.+-. 0.5
[0091] It was found from the above results that the use of a
polysaccharide solution having the following property renders
possible provision of a composition which facilitates its easy
administration due to reduced discharging force when the solution
is injected through thin catheter and needle using a syringe (it is
6.0 kgf or less when the catheter length is 1,650 mm and the needle
diameter is 21 G. and it is 10.0 kgf or less when the catheter
length is 2,300 mm and the needle diameter is 25 G) and which also
can keep protuberance of epithelium at such a height that treatment
of the epithelium can be easily carried out (average 5.0 mm or
more) for a certain period of time (30 minutes).
[0092] When measured using a rotational viscometer under a
condition of 25.degree. C., its viscosity at the following shear
rate is shown in Table 14 below.
TABLE-US-00014 TABLE 14 Shear rate (s.sup.-1) Viscosity (mPa s) 7.7
to 10.0 50 to 500 19.2 to 20.0 45 to 300 38.3 to 40.0 40 to 200
[0093] While the present invention has been described in detail and
with reference to specific embodiments thereof, it will be apparent
to one of skill in the art that various changes and modifications
can be made therein without departing from the spirit and scope
thereof. All references cited herein are incorporated in their
entirety.
[0094] This application is based on Japanese application No.
2001-339471 filed on Nov. 5, 2001, the entire contents of which are
incorporated hereinto by reference.
* * * * *