JPS6281319A - High-viscosity preparation for medical use - Google Patents

Abstract

PURPOSE:To provide the titled preparation containing carboxymethylated chitin as a component, available at an extremely low cost compared with sodium hyaluronate, having high decomposability, effective to minimize the post-operative increment of intraocular tension, etc., and useful especially as a protomerite infusion for the operation of anterior chamber. CONSTITUTION:Carboxymethylated chitin (abbreviated as CM-chitin) is a water- soluble chitin produced by converting chitin to alkali chitin and reacting with a monohalogenoacetic acid salt. CM-chitin especially having a carboxymethyl- substitution degree of about 1.0-2.5 per one monosaccharide residue is effective as a protomerite infusion for the operation of anterior chamber, a remedy for arthritis or an external coating agent for urinary catheter or insertion tube of gastric camera scope. Isotonic agent can be freely selected and no viscosity lowering occurs even by dry thermal sterilization. The safety of the present agent is comparable to or higher than that of sodium hyaluronate.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel highly viscous medical preparation, which can be used, for example, as an anterior chamber injection for anterior segment surgery or as a therapeutic agent for arthritis, etc. The present invention relates to medical high-viscosity preparations that are effective as anti-friction agents or lubricants for human mucous membranes, such as external coating agents for medical catheters and gastroscope insertion tubes, and suppository surface coating agents.

[Conventional technology]

BACKGROUND ART Conventionally, mucopolymerases represented by hyaluronate have been commonly used as medical lubricants. In addition, in recent years, during anterior segment surgery, such as cataract surgery, glaucoma surgery, corneal transplantation, and artificial intraocular lens implantation, a viscoelastic hyaluronate preparation is injected into the anterior chamber to perform surgical operations. It is used because it can prevent damage to the tissue surface, safely and reliably perform procedures such as suturing, and prevent adhesions after surgery.

However, currently, hyaluronate is relatively expensive because it is mainly extracted from cockscombs, vitreous body, etc., and the highly purified hyaluronate that is preferably used has a high purity due to the amount of protein contained in the raw material. It is also more expensive because it is difficult to remove.

In addition, when used as an anterior chamber injection for anterior eye surgery, the anterior eye area is washed to remove hyaluronate after surgery, but hyaluronate that is not completely removed remains in the anterior eye area. This has the disadvantage that it often remains in the intraocular tissue, which often causes an increase in intraocular pressure after surgery.

Furthermore, hyaluronic acid has the disadvantage that its viscosity decreases when heated, making it difficult to sterilize.On the other hand, chitin is widely distributed in the natural world, being found in crustaceans such as shrimp and crabs, and insects such as grasshoppers and beetles. It is widely distributed and is not difficult to purify, so highly pure products are commercially available at relatively low prices, but because it is insoluble in water, it cannot be used in highly viscous preparations such as those used for anterior segment surgery. .

[Problem that the invention seeks to solve]

An object of the present invention is to provide an inexpensive high-viscosity medical preparation.

[Means to solve the problem]

That is, the present invention relates to a highly viscous medical preparation containing chitin that has been made water-soluble by carboxymethylation.

Carboxymethylated chitin (hereinafter referred to as CM chitin) is obtained by converting chitin into alkali chitin and reacting it with a monohalogenoacetate.

The degree of carboxymethyl substitution of CM chitin can be changed by changing the amount of monohalogenoacetate relative to chitin, but if the degree of substitution is too small, it will not dissolve in water, and if it is too large, the viscoelasticity of the aqueous solution will be lost. A range of about 1.0 to 2.5 per saccharide residue is preferred.

The molecular weight of CM chitin depends on the molecular weight of the raw chitin, but if the molecular weight is too small, the viscosity will be low, so CM
The molecular weight of chitin is preferably 200,000 or more. Further, the preferred viscosity varies depending on the purpose of use, but for example, as a preparation for anterior segment surgery, the viscosity is about 10,000 to 15,000.
A range of 0 centistokes is preferred, and even about a
oooo to 120,000 centistokes is most preferred.

There is no significant difference in viscosity whether physiological isotonicity is achieved using a non-electrolyte or an electrolyte.
You can choose freely. Examples of electrolyte tonicity agents include:
Examples include sodium chloride, potassium chloride, etc., and examples of non-electrolyte tonicity agents include glycerin, ethylene glycol, glucose, mannose, and sorbitose. Furthermore, a bactericide or the like may be added as necessary.

The present invention will be explained in more detail with reference to examples below, but the present invention is not limited only to the examples.

〔Example〕

(Example 1) Powdered chitin (
Chitin-5S (trade name, manufactured by Shin Nihon Kagaku Co., Ltd.) was dispersed and kept under reduced pressure (20 mm/1 g) at room temperature for 5 hours to allow alkali to permeate the chitin. After cooling with ice, 500 g of ice was gradually added and stirred well to obtain an alkaline chitin solution.

To this alkaline chitin solution, add 210 g of sodium monochloroacetate dissolved in 240 g of water for 30 minutes at 5℃ or below.
Drop it over a few minutes, then keep it below 5℃ for 5 hours, then keep it at room temperature for 18 hours.
Allowed time to react. After neutralizing the reaction product with acetic acid, it was poured into ethanol to precipitate it, and then washed with a solution of ethanol:water=2:1 and dried.

After drying, it was reprecipitated with ethanol as a 1.5% aqueous solution.

The obtained carboxymethyl chitin sodium salt (hereinafter referred to as C
The amount of sodium was measured by atomic absorption spectrometry in an aqueous solution of M chitin Na), and the monosaccharide residue 1
Degree of carboxymethyl substitution per individual (hereinafter simply referred to as "degree of substitution")
It is called. ) was calculated, and the degree of substitution was 2.12.

(Examples 2 to 3) In order to obtain CM chitin pJa with different degrees of substitution, the amounts of sodium monochloroacetate were 57.4 g and 34.4 g, respectively.
The degree of substitution of CM chitin Na was measured in the same manner as in Example 1 except that the amount was 0 g. The measurement results are shown in Table 1 together with the measurement results of Example 1.

Table 1 (Example 4) CM chitin Na obtained in Example 1 (hereinafter referred to as CM-1) and CM chitin Na obtained in Example 3 (hereinafter referred to as CM-1)
3) was dissolved in physiological saline, and the viscosity and osmolarity at various concentrations were measured. In addition, for comparison, sodium hyaluronate (manufactured by Kewpie Finechemil Co., Ltd., trade name HA-S, hereinafter referred to as HA-8) was dissolved in physiological saline, and the viscosity and osmotic pressure at various concentrations were measured. The results are shown in Table 2. Note that cst hereinafter represents centistokes.

From this table, in order to obtain the same viscosity, CM with a large degree of substitution must be
Although the concentration of chitin Na needs to be slightly higher than that of HA-3, it is understood that CM chitin Na, which has a small degree of substitution, can be at approximately the same concentration as HA-S.

Table 2 (Example 5) In order to confirm the self-degradability of the residue after intraocular washing after surgery, the change in viscosity over time at low concentrations was measured. That is, C
M-1 was used as a 0.1% solution, and 0.05% HA was used as a comparison.
-S was used to observe changes in viscosity after storage at 40°C. The results are shown in Figure 1.

It can be seen that CM-1 has higher self-degradability than HA-3.

(Example 6) In order to confirm the safety of the residue after intraocular irrigation after surgery, a 0.1% aqueous solution of CM-1 and a 0.05% aqueous solution of HA-3 for comparison. Yong? (L) was filtrated and sterilized with a 0.45μ Millipore filter and used as an extract. The cell culture inhibition rate was measured according to the test method.The results were as follows.

0.1% CM-1 (Stored at 40°C for 2 weeks > 10.8%
0.05% HA-S (Stored at 40°C for 2 weeks) 1
The safety of the 3.3% preparation remaining after surgery is similar to that of sodium hyaluronate, or even safer than that of sodium hyaluronate.

(Example 7) In order to investigate the decrease in viscosity due to heat sterilization, CM-1 and HA-S as a comparative example were dry heat sterilized at 170°C for 20 minutes, and the viscosity of the aqueous solution before and after sterilization was measured. . The results are shown in Table 3.

Table 3 Note that the "viscosity reduction rate" was calculated using the following formula.

(Viscosity of treated part) While the viscosity of HA-3 decreased significantly, no decrease in viscosity was observed in CM chitin.

(Effect of the invention) The CM chitin of the present invention is (1) It is an extremely inexpensive preparation.

(2) The tonicity agent can be freely selected. That is, there is no difference in viscosity whether an electrolytic tonicity agent or a non-electrolytic tonicity agent is used, so either one can be used.

(3) Since it decomposes faster than sodium hyaluronate, it is possible to minimize the upper limit of intraocular pressure after surgery.

(4) When used as a preparation for anterior segment surgery, the safety of the preparation remaining after washing after surgery is the same as or safer than sodium hyaluronate.

(5) Viscosity does not decrease even after dry heat sterilization at 170°C for 20 minutes.

These effects have been recognized, making it very effective as a highly viscous medical preparation, particularly as an anterior chamber injection for anterior segment surgery.

[Brief explanation of drawings]

FIG. 1 is a graph showing changes in viscosity over time of a sodium hyaluronate aqueous solution and a carboxymethylated chitin aqueous solution. (Left below) Time (h ``) ・-・・ ・ ・ ・ ・ 0.05%HA -S○
-○・・・・・・0.1%CM chitin 1st
figure

Claims (2)

[Claims] (1) A highly viscous medical preparation containing carboxymethylated chitin. (2) The degree of carboxymethyl substitution of carboxymethylated chitin is approximately 1.0 to 2 per monosaccharide residue.
．． 5. The high viscosity medical preparation according to claim 1.