JPS63220865A - Vitreous body humor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a vitreous humor replacement fluid, and more particularly to a vitreous humor capture fluid that can substitute for or supplement the vitreous humor of the eyeball.

The m-body replacement fluid of the present invention can be used for removing the crystalline lens in the treatment of cataracts, inserting an artificial lens after removing the crystalline lens, and other ocular surgical operations.

[Technical background and explanation of conventional technology]

The space surrounded by the crystalline lens, ciliary body, and 'II5 membrane of the eyeball is bordered by a completely transparent, water-rich, soft, semi-liquid vitreous body. The vitreous body consists of thin and transparent 1iA cones, various connected cells, and vitreous humor, and the vitreous humor contains mucoids, urea, glucose, and various inorganic salts in addition to a small amount of protein.

(Kyoritsu Shuppan Co., Ltd., Chemistry Dictionary, Vol. 4, “Vitreous Body”) Opacification may occur in the vitreous body of the eye, and treatments such as vitreous aspiration and intravitreal injection of anterior aqueous humor may be necessary to treat this. Surgery was performed on the eyeball (Vitreous opacification, published by Nanzando, Medical Dictionary J, page 970), and the clouded crystalline lens was removed from the eyeball to treat cataract, which is a clouding of the lens of the eye. Surgery (published by Nanzando, “Medical Dictionary J”)
IE p. 1670 "Cataract"), surgery to insert an artificial lens after removing the crystalline lens, and lens dissection method to create a light path through the opacity of the crystalline lens. Surgical operations on the ball (“Medical Dictionary” published by Nanzando, No. 110)
Page 0 “Lentral dissection method”) is being performed.

Recently, when performing surgery on the eyeball, a highly viscous solution that does not cause inflammation or immunological rejection is injected into the eyeball to prevent tissue damage and undesirable adhesions after surgery. Attempts are being made to do so.

Chitosan is a polystyrene obtained by deacetylating chitin contained in the shells of crustaceans such as shrimp and crabs with concentrated alkali, and mainly consists of D-glucosamine.
Depending on the degree of deacetylation, D-glucosamine and N
- It is a complex multiamino acid consisting of acetyl-D-glucosamine.

It has been proposed to coat wounds with a lyophilized solution of chitosan to promote the recovery of tissue destroyed by the wound. (Patent Application No. 59-261807) The present inventors have been conducting research on chitin and chitosan for many years, but
In this research, it was found that chitin and chitosan are easily compatible with living organisms, and that no trouble occurs when chitin and chitosan come into contact with living tissue, and that N-carboxyacyl-F-san has a high viscosity and is highly biocompatible. We have discovered that scales form a transparent solution that does not cause troubles such as rejection reactions even when they come into contact with tissues, and based on these findings, we have arrived at the present invention.

[Object of the invention and summary of the invention]

An object of the present invention is to provide a vitreous fluid that can be injected into the eyeball. Specifically, the vitreous fluid is transparent, does not cause any trouble due to contact with living bodies, and can be used in eye treatment and surgery. The object of the present invention is to provide a vitreous fluid that can

The present invention is a vitreous fluid containing N-carboxyacylchitosan as an active ingredient, which is dissolved in a physiologically harmless solvent.

The N-carboxyacyl chitosan in the vitreous fluid of the present invention can be a substance represented by the general formula (!) above, and the N-carboxyacyl chitosan can be N-
Succinyl chitosan can be used, and N-carboxyacyl chitosan having a degree of substitution by carboxyacyl of 0.5 or more (preferably 0.6 to 0.9) can be used, and further, physiologically Non-hazardous solvents can be used, such as saline or phosphate buffered saline (pIi: 7.4).

(Detailed Description of the Invention) The N-carboxyacyl chitosan in the vitreous fluid of the present invention is obtained by deacetylating chitin obtained from the shells of crustaceans such as shrimp and crabs with a concentrated alkali. It is produced by chemically modifying the amino group with an acid halide or acid anhydride, and the degree of carboxyacyl substitution in the chemical modification is preferably 0.5 or more of the total amino groups of chitosan. It is more preferable to set it to 0.6 to 0.9.

Any dicarboxylic acid halide or acid anhydride, whether aliphatic saturated or unsaturated or aromatic, can be used, including succinic anhydride, maleic anhydride, Preference is given to using phthalic anhydride or its monohalides, such as its monochlorides or monofluorides.

The insulator fluid of the present invention is made by dissolving N-carboxyacyl chitosan in a physiologically harmless solvent. Components contained in the vitreous humor can also be added, thereby making the insulator fluid compatible with the living body.

Any solvent can be used to dissolve N-carboxyacyl chitosan as long as it is not physiologically harmful and can form a transparent solution, but physiological saline or Phosphate buffered saline solution (
Preference is given to using pH 77.4).

N-carboxyacylchitosan can be dissolved in a physiologically harmless solvent at any concentration that is not physiologically harmful, but it is preferably dissolved at a concentration of 1 to 5%.

The insulator replacement fluid of the present invention can be injected into the eyeball during eye surgery, thereby preventing damage to the tissue within the eyeball, and can also prevent the occurrence of a tubercle after surgery. Subsequent tissue separation can be ensured.

For example, it is suitable for use in cataract surgery, surgery for removing the crystalline lens, surgery for inserting an artificial lens into the eyeball, or surgery for drilling into the cloudy part of the crystalline lens.

The insulator replacement fluid of the present invention can be injected into the eyeball for curing eye diseases. For example, in the treatment of vitreous opacification, injecting the insulator fluid of the present invention into the eyeball can eliminate the vitreous opacification and promote recovery of visual acuity. When the insulator replacement fluid of the present invention is injected into the eyeball, it can promote the disappearance of bleeding and promote the recovery of visual acuity. Therefore, it can be used for the treatment of systemic diseases accompanied by vitreous hemorrhage, such as vitreous hemorrhage, vitreous hemorrhage, W disease, or third stage spirochete.

EXAMPLES Below, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (Preparation of chitosan) 20 kg of crushed red snow crab shell was mixed with 5% hydrochloric acid at 200 g.
1 and stirred at room temperature for 5 hours, the supernatant was separated and removed, and the residual solid was washed with water.

This solid was placed in a 5% aqueous sodium hydroxide solution 2001 and heated to 90° C. for 2.5 hours with stirring, then the supernatant was separated and the remaining solid was washed with water.

The chitin obtained here is dissolved in a 50% sodium hydroxide aqueous solution 2007! After heating at 90°C for 2.5 hours with stirring, the upper liquid a was separated and removed, the precipitated solid was thoroughly washed with water, and then heated at 95°C! 5 members, chitosan 4.1 to 9 was obtained.

(Preparation of N-succinyl chitosan) Six liquids of 5% chitosan were obtained by dissolving 16 g of chitosan in 5% acetic acid to give a concentration of 320-. 1.30% of methyl alcohol was added to 320% of this 5% chitosan solution, mixed well, and then filtered through a glass filter (151G3). A solution of succinic anhydride + 50 JI in 1.51 acetone was gradually added to the filtrate with stirring. After leaving it at room temperature for 24 hours, acetone and methyl alcohol were evaporated off using a rotary evaporator, and water
and adjust the pH to 10 with 5N aqueous sodium hydroxide solution.
I have adjusted it. Next, dialysis was performed for 4 days against ion-exchanged water.

Dilute the dialysate into 1. After passing through the membranes with pores of pore size of Opm, 0.6pm and 0.45pm respectively,
Freeze-vacuum drying yielded 23 g of N-succinylchitosan. The degree of substitution of the succinyl group in this N-succinyl chitosan was 0.8.

(Preparation of N-succinyl chitosan solution) 9 g of N-succinyl chitosan obtained above was added to 20 + nmol of N
a pH containing HPO and 150 mmol NaCl
: A 1.2% N-succinyl chitosan solution was obtained by dissolving it in a 7.4% phosphate buffered physiological saline solution to a concentration of 750.

This physiological saline solution had a viscosity of 4,400 centivoices, was clear, and did not contain pyrogens.

When the viscous, clear, pyrogen-free N-succinyl chitosan solution prepared in this way was injected into the anterior chamber of the rabbit's eye, it remained clear and showed only a minimal inflammatory reaction. It was demonstrated that it is useful as a vitreous substitute.

Example 2 (Preparation of N-glutaroyl chitosan a) 8 g of chitosan was dissolved in 5% acetic acid to a total volume of 160 mjl to obtain a 5% chitosan solution. 700 m of methyl alcohol was added to 160 m of this 5% chitosan solution. After adding and mixing thoroughly, filtration was performed using a glass filter (151G3). To the filtrate, 85 g of glutaric anhydride dissolved in 1 liter of methyl alcohol was gradually added with stirring. It was left at room temperature for 24 hours. Thereafter, methyl alcohol was removed by evaporation using a rotary evaporator, water lj was added, and the concentration was adjusted to 98 lO with a 5N aqueous sodium hydroxide solution.Next, dialysis was performed against ion-exchanged water for 4 days.

The dialysate was sequentially filtered through membranes having pores of 1.0 μm, 0.6 μm, and 0.45 μm, and then freeze-dried in vacuum to obtain log N-glutaroyl chitosan. The degree of substitution of the glutaroyl group in this N-glutaroyl chitosan was 0.75.

(Preparation of N-glutaroyl chitosan solution) The N-glutaroyl chitosan 2I obtained above was mixed with a solution containing 20 + amol of NaHPO and 150 ++nol of NaCl.
H: 200- to 7.4 phosphate-buffered physiological saline solution
A 1.0% solution was obtained. This physiological saline solution had a viscosity of 3,000 centivoids, was clear, and did not contain pyrogens.

When the viscous, transparent, pyrogen-free N-glutaroyl chitosan solution prepared in this way was injected into the anterior chamber of the rabbit's eye, it remained transparent and showed minimal inflammatory reactions. It was demonstrated that it is useful as a vitreous substitute.

Example 3 (Preparation of N-malonyylchitosan) A 5% chitosan solution was obtained by dissolving 8 g of chitosan in 5% acetic acid to give a concentration of 160-.This 5% chitosan solution 1
After adding 700 d of methyl alcohol to 60-ml and mixing well, the mixture was filtered through a glass filter (151G3). A solution of 73 g of maleic anhydride in Il of acetone was gradually diluted with stirring to the filtrate. That 2
After leaving the mixture at room temperature for 4 hours, acetone and methyl alcohol were removed by evaporation using a rotary evaporator, water +t was added, and the pH was adjusted to 1O with a 5N aqueous sodium hydroxide solution. Next, dialysis was performed for 4 days against ion-exchanged water. Dilute the dialysate into 1. opm, 0.6pm and 0.45
After sequentially filtering through membranes each having a pore size of 100 μm, 9.5 g of N-malonyylchitosan was obtained by freeze-vacuum drying. The degree of substitution of malonyyl groups in this N-malonyylchitosan was 0.78.

(Preparation of N-malonyylchitosan solution) 3 g of N-malonyylchitosan obtained above was mixed with 20 mmol of Na
pH 77 with HPO and +50 mmol NaCl
, 4 was dissolved in a 200% physiological salt solution to obtain a 1.5% solution. This physiological saline solution had a viscosity of 5.500 centivoise, was clear and pyrogen-free. When the viscous, transparent, pyrogen-free N-malonyylchitosan solution prepared in this way was injected into the anterior chamber of the rabbit's eye, it remained transparent and showed minimal inflammatory reactions. It was demonstrated that it is useful as a vitreous substitute.

Example 4 (Preparation of N-phthaloyl chitosan) 4 g of chitosan was dissolved in 5% acetic acid to give a solution of 80% chitosan to obtain a 5% chitosan solution. This 5% chitosan solution 80
＋＋＋j! After adding 400 d of methyl alcohol to the mixture and mixing well, the mixture was filtered through a glass filter (151G3). A solution of 55 g of phthalic anhydride dissolved in IJ methyl alcohol was gradually added to the filtrate with stirring.

After leaving it at room temperature for 24 hours, the methyl alcohol was removed by evaporation using a rotary evaporator, 500 g of water was added, and the pH was adjusted to IO with a 5N aqueous sodium hydroxide solution. Next, dialysis was performed for 4 days against ion-exchanged water.

Dilute the dialysate into 1. After filtration through membranes with pore sizes of opm, 00-6p and 0.45pm, respectively, 4.9 g of N-phthaloylchitosan was obtained by freeze-vacuum drying. The degree of substitution of the phthaloyl group in this N-phthaloyl chitosan was 0.75.

(Preparation of N-phthaloyl chitosan solution ia) 3 g of N-phthaloyl chitosan obtained above was mixed with 20 mmol of Na
pH with HPO and 150 mmol NaCl:
A 1.5% solution was obtained by dissolving it in a phosphate buffered physiological saline solution of 7.4 to a concentration of 200. This physiological saline solution had a viscosity of 8,900 centivoids, was clear and pyrogen-free.

The resulting viscous, transparent, pyrogen-free N-phthaloyl chitosan solution was injected into the anterior chamber of the rabbit eye, which remained transparent and showed only a minimal inflammatory response. It was demonstrated that it is useful as a vitreous substitute.

〔Effect of the invention〕

According to the present invention, in the chitosan derivative solution, the degree of substitution of the carboxyacyl group of N-carboxyacylchitosan is 0.
．． 5 or more and 1-5% (heavy ff) in buffered physiological saline solution.
Since it is dissolved at the concentration of 1), it is iso-strength, transparent, and viscous, and does not contain pyrogenic substances, making it useful in the treatment of ophthalmological diseases and surgical operations.

Furthermore, according to the present invention, the viscous solution is made by dissolving a chitosan derivative in an N-saturated physiological saline solution at a concentration of 1 to 5% (iiffi), and maintains a transparent state in the eyeball. Materials useful for the body can be obtained.

Japan Highoke S Cameles・'

Claims (5)

[Claims] (1) N-carboxyacylchitosan is used as an active ingredient,
A vitreous replacement fluid characterized in that N-carboxyacyl chitosan is dissolved in a physiologically harmless solvent. (2) N-carboxyacylchitosan has the general formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In formula (I), R is -(CH_2)_n・COO
H, (n is 0 to 7), -CH=CH・COOH, -CH
=CH-CH_2・COOH, -C_6H_4・COO
H, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. The vitreous replacement fluid according to claim 1, which has a repeating unit represented by: (3) Claim 2, characterized in that the N-carboxyacyl chitosan is N-succinyl chitosan.
Vitreous fluid replacement as described in section. (4) N-carboxyacyl chitosan is 0.6 to 0.
The vitreous replacement fluid according to claim 1 or 3, which has a degree of substitution of amino groups of 9. (5) Any one of claims 1 to 4, wherein the physiologically harmless solvent is physiological saline or a phosphate buffered physiological saline solution (pH: 7.4). Vitreous replacement fluid described in Crab.