Medical composition for protuberance of epithelium   

1. Field of the Invention

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.

2. Brief Description of the Background Art

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.

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.

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.

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.

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.

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

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.

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.

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 mPa·s at a shear rate of from 7.7 to 10.0 s−1; (2) from 45 to 300 mPa·s at a shear rate of from 19.2 to 20.0 s−1; and (3) from 40 to 200 mPa·s at a shear rate of from 38.3 to 40.0 s−1,

when measured using a rotational viscometer at 25° C. (hereinafter referred to as “composition of the present invention”).

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”).

Moreover, these and other objects of the present invention have been accomplished by a method for resecting epithelium, which comprises:

administering an effective amount of the medical composition to under epithelium to thereby obtain protuberance of the epithelium; and

resecting the protuberance.

DETAILED DESCRIPTION

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.

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° 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).

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.

The polysaccharide used in the composition of the present invention is preferably a glycosaminoglycan, and the glycosaminoglycan is preferably hyaluronic acid.

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.

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)).

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.

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° C.

TABLE 1 Shear rate (s−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

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.

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.

The present invention is specifically described with reference to the case in which hyaluronic acid is used as the polysaccharide.

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.

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 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

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).

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 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

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