JPH10290830A - Adjuvant for operating on eye - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a highly viscous adjuvant which is comparatively stable at a room temperature and under heating and is suitable for operation on an eye such as cataract surgery, intraocular lens transplant surgery, glaucoma surgery and penetrating keratoplasty. SOLUTION: This adjuvant contains at least one kind of a viscosity stabilizer selected from a group composed of (A) a hyaluronic acid and/or hyaluronic acid salt and (B) a polyacroboxylic acid and its salt, polyol, carbohydrate and an amino acid and its salt. It is composed of an aqueous solution on which viscosity at 37 deg.C is 20,000 centipoise to 200,000 centipoise.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an auxiliary for eye surgery such as cataract surgery, intraocular lens transplantation surgery, glaucoma surgery and full-thickness corneal transplantation surgery. More specifically, the present invention relates to an auxiliary for eye surgery which is relatively stable even at room temperature and under heating.

[0002]

[Prior Art] In recent years, the number of patients with various eye diseases has increased along with the increase of the elderly, and the development of effective pharmacotherapy methods and simple and safe surgical methods will continue to be increasingly important in the future. Become. Among them, the development of new surgical modalities of cataract surgery, intraocular lens insertion surgery and glaucoma surgery has made remarkable progress year by year, and has become a gospel for patients. In cataract surgery, simplification of the operation, reduction of the incision site, improvement of the intraocular lens, and advancement of the insertion technique have been used after surgery, by using ultrasonic emulsification and other techniques to crush and remove the opaque lens. Progress has been improved,
Day surgery was also possible.

[0003] In order to carry out the above-mentioned surgery smoothly and safely, a viscoelastic preparation used as an auxiliary for surgery plays an important role. That is, by injecting the surgical adjuvant into the eye from the incision site during surgery, the space in the anterior chamber and posterior chamber is maintained, the tissue and endothelial cells are protected from mechanical damage, and the surgical instruments and intraocular lens are easily used. Insert,
Effects such as minimizing bleeding are obtained. Hyaluronic acid or its salts, chondroitin sulfate or its salts, methylcellulose, etc. are currently used clinically as the main components of these surgical adjuvants. Among them, an aqueous solution of sodium hyaluronate is particularly used as a main component of the viscoelastic preparation because it has high viscoelasticity necessary for maintaining an intraocular space and has biosafety.

The chemical structure of sodium hyaluronate is such that sodium glucuronate and N-acetylglucosamine are β
It is a high molecular polysaccharide having repeating units of 1 → 3 and β1 → 4 linkage. This substance is distributed in connective tissues such as cartilage and joints of mammals, vitreous body of eye, cockscomb and the like. In recent years, the substance can be obtained by producing microorganisms such as Streptococcus. Natural sodium hyaluronate is
When present in a living body, its average molecular weight is 8,000,000 to 1
It is said to be 3 million, and its molecular weight is usually 20,000 to 50, because it is successively reduced in molecular weight during its isolation and purification.
100,000 products will be available.

[0005] The molecular weight range of the present preparation currently used clinically for ophthalmic surgery is ultra-high molecular weight (about 500
10,000), high molecular weight (1.9-3.9 million), medium molecular weight (1
500,000-2.1 million) and low molecular weight (600,000-120,000)
10,000). Clinical evaluation has both advantages and disadvantages due to these differences in molecular weight and viscosity. Of these, medium-viscosity formulations composed of low- or medium-molecular-weight sodium hyaluronate reduce postoperative intraocular pressure rise and the occurrence of inflammation, And the rate of endothelial cell reduction is low. on the other hand,
A highly viscous formulation composed of an ultra-high or high molecular weight makes it easy to insert the intraocular lens because the anterior chamber space can be maintained firmly, and also facilitates the removal of the used hyaluronic acid formulation ( Surv . Ophthalmol ., 34 268
P. 1990, and ophthalmic surgery 6 p.
3 years).

[0006] The powdered substance, when used for the above-mentioned purpose of use, must be dissolved in physiological saline, phosphate, borate or Tris buffer. However, the hyaluronic acid in such an aqueous solution state is gradually degraded at room temperature and rapidly under heating conditions, and the viscosity (or intrinsic viscosity) is also reduced accordingly. Therefore, most of the market products must be stored in a cool and dark place for a long period of time, and the labor and the distribution cost at the time of product distribution cannot be ignored. In addition, the heat sterilization operation, which is important in the preparation process, is complicated, such as the intermittent sterilization method, and much care is required to prevent the molecular weight of the main component from being reduced.

As for the method of stabilizing the aqueous solution of sodium hyaluronate, a method of coexisting a compound having a phenolic hydroxyl group (see JP-A-1-113401) and a method of adding a polymer such as polyamino acid and polyacrylic acid (See JP-A-57-185208), but the viscosity of the preparation is 100 centipoise (c).
p), the results were low, and satisfactory results were not obtained in both stability and viscosity. Furthermore, it is known that polyhydric alcohols, monosaccharides and sugar alcohols are added to an aqueous solution of hyaluronic acid as other viscosity stabilizers and applied to cosmetics and cosmetic lotions (JP-A-55-1537).
No. 11 and JP-A-61-180705).

Also, preparation of a highly viscous hyaluronic acid preparation using a non-electrolyte thickening agent selected from the group consisting of polyhydric alcohols, sugar alcohols, glucose and mannose is known (Japanese Patent Publication No. 1-224824). reference).
This preparation, as described in the same publication, by using a high-viscosity preparation, in the anterior segment surgery, to prevent damage to the tissue surface, safely and reliably perform procedures such as suturing,
Another object is to prevent postoperative adhesions.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide an auxiliary for eye surgery. Another object of the present invention is to provide an auxiliary for ophthalmic surgery comprising a stable and highly viscous preparation of an aqueous solution of hyaluronic acid. Still another object of the present invention is to contain a viscosity stabilizer, thereby being excellent in storage stability over a long period of time at room temperature, and can prevent extremely low viscosity under normal heat sterilization conditions. It is to provide an auxiliary for eye surgery. It is yet another object of the present invention to provide the use of certain compounds as viscosity stabilizers in eye surgery adjuvants. Still other objects and advantages of the present invention will become apparent from the following description.

[0010]

Means for Solving the Problems The present inventors have intensively searched for a viscosity stabilizer in order to solve the above-mentioned problems. As a result, a specific polycarboxylic acid, a specific polycarboxylic acid, By adding at least one of polyols, carbohydrates and amino acids, it has been found that the viscosity of the aqueous solution can be suppressed from being lowered, and that the present invention exhibits viscosity stability at room temperature and under heating for a long period of time, and has completed the present invention.

That is, according to the present invention, the above objects and advantages of the present invention are as follows: (A) hyaluronic acid and / or hyaluronic acid salt; and (B) polycarboxylic acid and its salt, polyol, and sugar. And at least one viscosity stabilizer selected from the group consisting of amino acids and salts thereof, and having a viscosity at 37 ° C. of 2
This is achieved by an ophthalmic surgery adjuvant characterized in that it comprises an aqueous solution that is at least 000 centipoise and less than 200,000 centipoise.

The hyaluronic acid used in the present invention preferably has a number average molecular weight in the range of 600,000 to 3.9 million. As the salts of hyaluronic acid, sodium salts, potassium salts, basic amino acid salts and the like are used. Among them, sodium salts are particularly preferable for preparations used for ophthalmic surgery, in view of the vitreous body composition and the salt composition of aqueous humor. The concentration of hyaluronic acid and its salt in the aqueous solution preparation of the present invention is appropriately determined according to the viscosity for the purpose of use, but is preferably 0.5 to 5.0% by weight.
Within the range.

The viscosity stabilizers used in the present invention are polycarboxylic acids and salts thereof, polyols, carbohydrates and amino acids and salts thereof. These can be used alone or in combination of two or more. These viscosity stabilizers are water-soluble and contribute to stabilization of the aqueous solution of the present invention. In the present invention, the viscosity stability test over time is evaluated by measuring the viscosity using a rotational viscometer.

As the polycarboxylic acid and its salt, sodium citrate and carboxyvinyl polymer are preferably used. These can be used alone or in combination. The polycarboxylic acids and salts thereof are preferably used at a concentration of 0.05 to 1.0% by weight.

[0015] As the polyol, ethylene glycol, propylene glycol, glycerin, polyvinyl alcohol and polyethylene glycol are preferably used. These can be used alone or in combination of two or more. The polyol is used in a concentration of preferably 0.5 to 10.0% by weight, more preferably 1.0 to 2.5% by weight.

As saccharides, sorbitol, trehalose, sucrose, carboxymethylcellulose and β-cyclodextrin are preferably used. These can be used alone or in combination of two or more. The carbohydrate is preferably used at a concentration of between 0.05 and 5.0% by weight.

Histidine, arginine and sodium aspartate are preferably used as amino acids. These can be used alone or in combination of two or more. Amino acids are preferably used at a concentration of between 0.05 and 1.0% by weight.

The aqueous solution of the present invention contains hyaluronic acid and / or
Alternatively, it is prepared by dissolving sodium hyaluronate (A) and a viscosity stabilizer (B) in an aqueous solvent. As the aqueous medium, purified water, an aqueous solution in which an isotonic agent is dissolved, or an aqueous solution in which a buffer is dissolved are preferably used. The tonicity agent or buffer is preferably prepared by dissolving it in purified water at 2% by weight or less.

As the tonicity agent, sodium chloride and potassium chloride are preferred. Examples of the buffer include a phosphate buffer such as sodium dihydrogen phosphate and sodium monohydrogen phosphate, a boric acid buffer such as borax and boric acid, and a tris buffer such as trisaminomethane and dilute hydrochloric acid or trismalate and dilute caustic soda solution. Agents are preferred.
The pH range of the aqueous solution of the present invention is preferably from pH 6 to pH 8. In the acidic region of pH 6 or lower or the alkaline region of pH 8 or higher, hydrolysis greatly reduces the viscosity, and should be avoided. Further, the osmotic pressure of the aqueous solution of the present invention,
When the concentration of the tonicity agent is adjusted so that the physiological saline is 1, it is preferable that the osmotic pressure ratio falls within the range of 0.7 to 1.3.

According to the present invention, the viscosity-stabilized preparation thus obtained is subjected to a stability test over time. As a result, assuming that the initial value of viscosity is 100%, the preparation containing glycerin as a viscosity stabilizer is Storage at 52 ° C. for 2 weeks showed a viscosity retention of 90% or more, and significantly improved stability compared to the comparative example without glycerin, so that long-term storage at room temperature was possible. In addition, a high-temperature test of the preparation by heat treatment at 100 ° C. for 40 minutes similarly showed a viscosity retention of 90% or more, thereby enabling one-step heat sterilization.

The aqueous solution of the present invention has a viscosity range of 20,000 centipoise to 200,000 centipoise at 37 ° C., which is the optimum temperature of the adjuvant used in cataract surgery, intraocular lens transplantation surgery, glaucoma surgery and full thickness corneal transplantation surgery. Less than 000 centipoise. By appropriately selecting the molecular weight and concentration of hyaluronic acid and the type and concentration of the viscosity stabilizer, a desired viscosity preparation can be easily prepared. Therefore, according to the present invention, the above-mentioned polycarboxylic acids and salts thereof, polyols, carbohydrates, amino acids and amino acids thereof as viscosity stabilizers of ophthalmic adjuvants containing hyaluronic acid and / or hyaluronic acid salts are furthermore provided. There is provided the use of a compound selected from the group consisting of salts.

[0022]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Example 1 and Comparative Example 1 Sodium hyaluronate (average molecular weight: 2) was added to a physiological phosphate buffer containing 1.4% by weight of propylene glycol.
300,000) was heat-treated at 100 ° C. after melting at 1.5% by weight, and the viscosities before and after the heat treatment were measured using a rotational viscometer.
It was measured at a shear rate of 1 / sec. Table 1 shows the measured values and the viscosity retention ratio when the viscosity before heat treatment was taken as 100%. As a control, a sample to which no propylene glycol was added was measured in the same manner as Comparative Example 1.

[0023]

[Table 1]

Example 2 and Comparative Example 2 Sodium hyaluronate (average molecular weight 2.3 million) was added to a physiological phosphate buffer containing 2.0% by weight of sorbitol.
Was melted at a temperature of 115 ° C., and the viscosities before and after the heat treatment were measured at a shear rate of 4 using a rotational viscometer.
/ Sec. Measured value and viscosity before heat treatment are 100
% Are shown in Table 2. As a control, a sample to which no sorbitol was added was similarly measured as Comparative Example 2.

[0025]

[Table 2]

From the results shown in Table 2, it can be seen that the addition of sorbitol suppresses a decrease in the viscosity of the aqueous solution of sodium hyaluronate.

Example 3 and Comparative Example 3 A carboxyvinyl polymer, that is, a physiological phosphate buffer containing 0.3% by weight of polyacrylic acid was added with 2.0% by weight of sodium hyaluronate (average molecular weight: 1,000,000).
After dissolving and heat-treating at 100 ° C. for 20 minutes, the solution was stored at 52 ° C., and the viscosities immediately after storage, 3 days after storage, 7 days after and 14 days after storage were measured using a rotational viscometer at a shear rate of 4 / sec. Table 3 shows the measured values and the viscosity retention when the viscosity immediately after storage was taken as 100%. As a control, the same measurement was performed as Comparative Example 3 except that no carboxyvinyl polymer was added.

[0028]

[Table 3]

From the results in Table 3, it can be seen that the addition of the carboxyvinyl polymer suppresses the decrease in the viscosity of the aqueous solution of sodium hyaluronate.

Example 4 and Comparative Example 4 1.5% by weight of sodium salt of hyaluronic acid (average molecular weight: 2.3 million) was dissolved in a physiological phosphate buffer containing 2.4% by weight of glycerin, and then dissolved at 100 ° C. for 20 minutes. After heat treatment,
Store at 52 ° C, immediately after storage, 3 days after storage, 7 days after storage, 14 days after storage.
The viscosity after one day was measured at a shear rate of 4 / sec using a rotational viscometer. Table 4 shows the measured values and the viscosity retention when the viscosity immediately after storage was taken as 100%. In addition, the same measurement was performed as Comparative Example 4 except that glycerin was not added as a control.

[0031]

[Table 4]

From the results shown in Table 4, it can be seen that the addition of glycerin suppresses the decrease in viscosity of the aqueous solution of sodium hyaluronate.

Example 5 and Comparative Example 4 1.5 weight% of hyaluronic acid sodium salt (average molecular weight 2.3 million) was added to a physiological phosphate buffer containing 0.1% by weight of lysine and 0.85% by weight of sodium citrate. %, And heat-treated at 100 ° C. for 20 minutes, and stored at 52 ° C.
Immediately after storage, 3 days, 7 days, and 14 days after storage, viscosities were measured using a rotational viscometer at a shear rate of 4 / sec. Table 5 shows the measured values and the viscosity retention ratio when the viscosity immediately after storage was taken as 100%. In addition, the same measurement was carried out for a control without addition of lysine and sodium citrate.

[0034]

[Table 5]

From the results in Table 5, it can be seen that the addition of lysine and sodium citrate suppresses a decrease in viscosity of the aqueous solution of sodium hyaluronate.

[0036]

Industrial Applicability The present invention provides a relatively stable ophthalmic solution by adding a specific polycarboxylic acid and its salt, a polyol, a saccharide and an amino acid, which are viscosity stabilizers, to an aqueous solution of hyaluronic acid and / or its salt. A highly viscous hyaluronic acid preparation for surgery could be prepared, thus allowing long-term stable storage of the product at room temperature and one-step heat sterilization.

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[Procedure amendment]

[Submission date] April 22, 1997

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction contents]

Histidine, arginine and sodium aspartate are preferably used as amino acids and salts thereof . These can be used alone or in combination of two or more. Amino acids are preferably 0.05 to 1.
It is used at a concentration of 0% by weight.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Yasushi Takahashi 410-6 Shimomizo, Sagamihara City, Kanagawa Prefecture

Claims (6)

[Claims] 1. A viscosity stabilizer selected from the group consisting of (A) hyaluronic acid and / or a hyaluronic acid salt, and (B) a polycarboxylic acid and its salts, polyols, saccharides, and amino acids and its salts. And an aqueous solution having a viscosity at 37 ° C. of not less than 20,000 centipoise and less than 200,000 centipoise. 2. The aid for ophthalmic surgery according to claim 1, wherein the polycarboxylic acid and its salt are selected from the group consisting of sodium citrate and carboxyvinyl polymer. 3. The eye surgery aid according to claim 1, wherein the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerin, polyvinyl alcohol and polyethylene glycol. 4. The method according to claim 1, wherein the saccharide is selected from the group consisting of sorbitol, trehalose, sucrose, carboxymethylcellulose, and β-cyclodextrin. 5. The method according to claim 1, wherein the amino acid and its salt are selected from the group consisting of histidine, arginine and sodium aspartate. 6. A polycarboxylic acid and its salts, polyols, carbohydrates and amino acids and its salts as a viscosity stabilizer of an auxiliary agent for ophthalmic surgery containing hyaluronic acid and / or hyaluronate. Use of compounds.