JPS62266056A - Viscoelastic solution for ophthalmic operation - 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 [Field of Application] The present invention relates to a viscoelastic solution for ophthalmic surgery, which is a thickening agent used during ophthalmic surgery.

The viscoelastic solution for ophthalmic surgery of the present invention can be injected into the anterior chamber or retrograde lens capsule during cataract surgery, intraocular lens insertion surgery, corneal transplantation surgery, and other ophthalmic surgeries, to protect the corneal endothelium and protect the anterior chamber. It can be used to measure the formation of water, posterior aqueous humor, etc.

(Prior art and its problems) Conventionally, during cataract surgery, intraocular lens insertion surgery, corneal transplant surgery, ocular trauma surgery, and glaucoma surgery, M+ tissues such as corneal endothelial cells are protected from instruments, and the anterior chamber space is A 1% sodium hyaluronate solution is used to preserve the water and for other purposes.However, sodium hyaluronate is a natural product extracted from cockscombs, etc., so it is expensive, difficult to purify, and difficult to sterilize. This makes it extremely expensive, and there is also the problem of poor stability and deterioration.

The use of chondroitin sulfate has also been attempted, but it requires a high concentration of about 20% to increase viscosity.
There was a problem in that the osmotic pressure increased and the cornea swelled.

On the other hand, attempts have been made to use cellulose ether solutions as cheaper viscous substances. As the cellulose ether, methylcellulose or hydroxypropylmethylcellulose is used. However, what has been conventionally used is a solution with a weight average molecular weight of less than 1i400,000 and a concentration of 1 to 2.5%, which does not have sufficient viscosity and is inferior to sodium hyaluronate in its suitability for manual handling. Ta. Therefore, if the concentration is increased to increase the viscosity, filtration becomes difficult and formulation cannot be made, and if the molecular weight is increased, there are problems such as an increase in intraocular pressure, making it difficult to put it into practical use.

[Means for solving problems]

As a result of intensive research, the present inventors have found that by using a hydroxypropyl methylcellulose solution having the following specific composition, molecular weight, molecular weight distribution, and concentration, it is possible to create a solution that is inexpensive, easy to formulate, and has a high viscosity. It has been found that it has the same or higher effect as sodium hyaluronate without causing any problems such as increased intraocular pressure.

That is, the present invention has a methoxy group content of 28 to 32%, a hydroxyl group content of 7 to 12%, a weight average molecular weight (M) of 420,000 to 800,000, and a ratio of the weight average molecular weight to the number average molecular weight (MN) ( M,,/MN
) 5.5 or less hydroxypropyl methyl cellulose in the concentration range defined by the following formula, natural logarithm of maximum concentration: ffogc14Ag = 0. 64 0. 005
A viscoelastic solution for ophthalmic surgery is provided which is dissolved in water containing saline such that the natural logarithm of the minimum concentration of 5M is: NOgCM+N=0.57 0.0071M.

Preferably, when the solution concentration of hydroxypropyl methyl cellulose is approximately 0.02%, the number of fine particles of 2 μm or larger measured by an electrical resistance method is 250.
The present invention provides a viscoelastic solution for ophthalmologic surgery in which the number of fine particles of 4 ttm or more is 20 particles/m1 or less.

Hydroxypropyl methylcellulose in the present invention will be explained below.

Hydroxypropyl methylcellulose has a methoxy group content of 28 to 32% and a hydroxypropoxy group content of 7 to 32%.
Preferably it is 12%.

If the methoxy group content is lower than 28%, solubility decreases, resulting in an increase in the number of fine particles (microgel) in the solution, resulting in poor filterability during formulation.

Furthermore, if fine particles (microgel) remain, they cause problems such as increased intraocular pressure. If the methoxy group content is 32% or more, the hydrophilicity is insufficient, which is not preferable. When the hydroxypropoxy base M is lower than 7%, the number of fine particles (microgel) in the solution increases, resulting in poor filterability. Furthermore, since the fluidity of the solution in the capillary becomes poor, it becomes difficult to extrude it from a syringe, making it impractical. It is difficult to synthesize those with a hydroxypropoxy group content of 12% or more.

Weight average molecular weight (M8) is 42QOOOO~8oooo
It is preferably in the range of o.

The weight average molecular weight is determined by measuring the intrinsic viscosity [η] using, for example, an Ubbelohde viscometer, and calculating Mw from the following formula.

[η) -3,67X I O-'Mtn'-
``If the weight average molecular weight is lower than 420,000, the viscosity of the solution is not high enough, and its use as a viscoelastic solution for ophthalmic surgery is limited.Furthermore, if the concentration is increased in an attempt to increase the viscosity of the solution, filtration becomes extremely difficult. Therefore, it cannot be formulated into a formulation.

If the weight average molecular weight exceeds 800,000, it is undesirable because it tends to cause an increase in intraocular pressure, the time it remains in the anterior chamber etc. becomes longer, and the ease with which it is washed out from the anterior chamber etc. decreases. Particularly desirable is 500,000 to 7,000.
It is 00.

Weight average molecular weight ( for number average molecule 'ft (MN>)
The ratio (M,/MN) of M, 4) is preferably 5.5 or less.

Weight average molecular weight (M, ) to number average molecular weight (MN)
The ratio (M, /MN) can be determined by gel permeation chromatography (GPC). However, in the present invention, the column is TS K gel G M P
Using two Wxt (manufactured by Toyo Soda Co., Ltd.), the sample was 0.
0.1M Na containing 02% NaN3.

SO was made into an aqueous solution and measured at a flow rate of 1 m 127 m1n and a temperature of 25°C to determine the average molecular weight.

The weight average molecular weight is 420,000 or more.

When /MN exceeds 5.5, the filterability of the solution becomes poor and the intraocular pressure tends to increase. Because, M.
When l/MN becomes large, even if the weight average molecular weight is the same, M
This is thought to result in poor filtration and increased intraocular pressure, since more high molecular weight moieties are present than in the case where 11/MN is small.

Particularly desirable is 5.2 or less.

Hydroxypropyl methylcellulose has a concentration range defined by the following formula: Natural logarithm of maximum concentration: 10gCHAx = 0.64 0.0055M Natural logarithm of minimum concentration: 10gCs+N=0. 57 0. It is preferable to dissolve it in water containing salts so that it becomes 0.0071M.

If the maximum concentration (C)IA or %) is exceeded, the intraocular pressure increases, the residual time in the anterior chamber becomes longer, and it becomes difficult to wash out after the surgery, which is undesirable.

If the concentration is below the minimum concentration (C1lI8, %), the viscosity of the solution decreases, and its use as a viscoelastic solution for ophthalmic surgery is significantly limited.

Only when the above four requirements, namely methoxy group content, hydroxypropoxy group content, average molecular weight, molecular weight distribution, and concentration range of hydroxypropyl methylcellulose are all met, can the formulation be easily formulated; and ■ reduce intraocular pressure. It is possible to achieve the following objectives: (1) reducing the residual time in the anterior chamber and during retroversion and making it easier to wash out; and (2) providing a high viscosity that is effective as a viscoelastic solution for ophthalmic surgery.

Hydroxypropyl methylcellulose having excellent solubility as defined above is used, but it is necessary to keep the number of fine particles below a certain number in order to avoid problems such as an increase in intraocular pressure. Preferably, when the solution concentration of hydroxypropyl methyl cellulose is approximately 0.02%, the diameter is 2 μm or more as measured by an electrical resistance method.
- It is preferable that the number of fine particles of 2500 pieces/7ml or less, and the number of fine particles of 4 μm or more is 20 pieces/n or less.

In the present invention, the number of microparticles in a solution is determined by CoulterE.
Coul manufactured by Electronics TNC, Inc.
It was measured by an electrical resistance method using a ter Count-erTA-H type. The hydroxypropyl methylcellulose solution is diluted with saline and measured as 0.02%.

An aperture of 50 μm is used. When the aperture is
i! When a particle is present, a change occurs in the electrical resistance between the electrodes on both sides, and this can be detected to determine the particle size.

The number of particles determined by Coulter Counter is 2,500 particles/m7 of particles larger than 2 μm! Below, 4
20 pieces/m I! If the amount is higher than this, problems such as an increase in intraocular pressure by 1% are likely to occur.

In order to reduce the number of fine particles, it is usually preferable to repeat filtration using a 0.8 μm membrane filter.
Preferably, filtration is carried out 5 times to 5 times.

〔Effect of the invention〕

Viscoelasticity for 44 ophthalmological hands of the present invention? fI liquid has the following effects.

(1) Compared to sodium hyaluronate, ■ It is extremely inexpensive.

■ Chemically stable and unaffected by heat, light, etc.
Autoclave sterilization is possible.

■Tonicity agent can be freely selected.

■ The clinical effect is equivalent or better than that of a viscoelastic solution for ophthalmic surgery.

The following effects were observed.

(2) Conventional methylcellulose or hydroxypropylmethylcellulose, etc., have a higher viscosity than preparations made of conventional methylcellulose or hydroxypropylmethylcellulose, so when used as a viscoelastic solution for ophthalmic surgery, it is difficult to It is extremely superior in terms of forming ability and ease of inserting intraocular lenses.

Particularly in the case of in-the-bag intraocular lens insertion, surgery that is difficult to perform with conventional preparations made of methylcellulose or hydroxypropylmethylcellulose becomes possible. Furthermore, since it has a high structural viscosity, it is easy to extrude from an injection needle despite its high viscosity.

■Safety such as intraocular pressure, residence time in the anterior chamber, and ease of washing out from the anterior chamber is equivalent to conventional preparations made of methylcellulose or hydroxypropylmethylcellulose.

The following effects were observed.

Therefore, the viscoelastic solution for ophthalmic surgery of the present invention can be injected into the anterior chamber or retrograde lens capsule during cataract surgery, intraocular lens insertion surgery, corneal transplantation surgery, and other ophthalmic surgeries to protect the corneal endothelium. It can be used extremely effectively to measure the formation of the anterior chamber, the formation of retrogression, etc.

〔Example〕

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited only to these examples.

Example 1 Methoxy group content 29.5%, hydroxypropoxy group content 10.6%, weight average molecular weight? 20000, Mw /
Hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical) with MN = 4.5 was dissolved in physiological saline to give a concentration of 1.8%.
A solution was prepared. This was repeatedly filtered three times using a 0°8 μm membrane filter. The viscosity of the obtained solution at 20° C. (by a B-type viscometer, rotation speed 12 rpm) was 20,900 cps.

Using this solution, in a state where the intraocular pressure of the isolated pig eye was increased,
When a retrograde intraocular lens insertion test using the bag method was performed, the retrograde formation ability was excellent and the lens insertion was easy.

Comparative Example 1 <When the concentration of hydroxypropyl methylcellulose is low) A 1.1% physiological saline solution of hydroxypropyl methylcellulose similar to that in Example 1 was prepared and filtered in the same manner. The viscosity of the obtained solution at 20°C is 2010 cp
It was s. Using this solution, a retrograde intraocular lens insertion test was conducted in the same manner as in Example 1. As a result, there was no retrograde formation ability, and lens insertion was difficult.

Ratio 1112 <When the molecular weight of hydroxypropyl methylcellulose is low) Methoxy group content 29.6%, hydroxypropoxy group content 10.8%, weight average molecule 1g1o.

Hydroxypropyl methyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) having a concentration of 0.00 and Mw/MN = 6.2 was dissolved in physiological saline in the same manner as in Example 1 to prepare a 2.0% solution, which was filtered. The viscosity of the obtained solution at 20°C was 4010 cps. Using this solution, Example 1
When a posterior chamber intraocular lens insertion test was performed in the same manner as above,
Insertion of the lens was difficult due to insufficient retrograde ability.

Example 2 The same hydroxypropyl methylcellulose as in Example 1 was dissolved in physiological saline to a concentration of 1.6%, and the viscosity (
20° C.) A solution of 11,500 cps was prepared. Set this to 0
．． When filtering with an 8 μm membrane filter at a constant pressure of 3 kg/cm, clogging occurred the first time as shown in Figure 1, but from the second time onwards, it was easy to filter and there were no problems with the formulation. .

Comparative Example 3 (Increasing the viscosity by increasing the concentration of hydroxypropyl methylcellulose with a low molecular weight) The same hydroxypropyl methylcellulose as in Comparative Example 2 was dissolved in physiological saline to a concentration of 2.9%, and the viscosity (
(20°C) 11,300 cps solution was prepared. When this solution was filtered in the same manner as in Example 2, as shown in Fig. 2, even if the number of filtrations was increased, the filtration performance did not improve at all, making it difficult to formulate a formulation.Example 3 Methoxy group content: 29.2 %, hydroxypropoxy group content 10.1%, weight average molecular weight 520000, Mw/M
Hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical) with N=4.9 was dissolved in physiological saline to prepare a 2.0% solution. This was repeatedly filtered three times using a 0°8 μm membrane filter. The viscosity of the obtained solution at 20°C was 10,100 cps.

In addition, this solution was diluted with physiological saline to make a 0.02% solution, and the Coulter Counter T A
-The number of fine particles measured using a TI type using a 50 μm aperture was 933 particles/m of 2 μm or larger, 1.4 μm.
There were 16 pieces/ll1p of those with m or more. After suctioning 0.2 m# of anterior aqueous humor from a rabbit eye, 0.2 ml of this solution was injected, and the intraocular pressure was measured. 4 hours f! 13mn+Hg to 25
I saw an increase in intraocular pressure to mmHg, but it was not enough to cause a problem.
After 24 hours, it was almost back to its original state.

Comparative Example 4 (When there are many fine particles) A solution prepared in the same manner as in Example 3 was filtered once with a 1.2 μm membrane filter. When the number of fine particles in this solution was measured in the same manner as in Example 3, the number of particles larger than 2 μm was 2830 particles/ml! , those with a diameter of 4 μm or more are 62
It was 111 pieces/111 pieces. This solution was injected into the anterior chamber of a rabbit's eye in the same manner as in Example 3, and the intraocular pressure was measured. After 4 hours, the intraocular pressure increased from 13 mmHg to 45 mmHg. This intraocular pressure returned to almost its original state after 24 hours.

Comparative Example 5 (When the methoxy group content of hydroxypropyl methyl cellulose is low) Methoxy group content 21.2%, hydroxypropoxy group content 6.7%, weight average molecular weight 570000, M, 1/
Hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) with MW = 4, 7 was dissolved in physiological saline, and 1.8
% solution was prepared. The viscosity at 20°C is 1030
It was 0 cps. When the obtained solution was filtered with a 0.8 μm membrane filter at a constant pressure of 3 kg/cI112, it was so clogged that filtration was impossible.

Example 4 and Comparative Example 5 (When the molecular weight of hydroxypropyl methylcellulose is low) During intraocular lens surgery, the cellulose ether solution injected into the eye is washed out with an irrigation solution. The following experiment was conducted to examine the ease of washing out.

Pour 2.0 mj of sample solution into a 2-vall volumetric pipette! Attach a silicone tube with a suction inner diameter of l, and flow distilled water for 20011n at a rate of 28 mIl/sin using a microtube pump, receive the solution in a beaker, evaporate to dryness, and quantify the elution amount of cellulose ether. The residual amount was determined. The experimental results are shown in Table 1.

However, in Example 4, the same solution as in Example 2 was used as the sample solution (Sample A), and in Comparative Example 5, the same hydroxypropyl methylcellulose as in Comparative Example 2 was added to physiological saline at a concentration of 2.5%. The solution was dissolved and filtered and used as a sample solution (referred to as sample B).

Table 1 From this result, compared to sample A, sample B has a less
＜, it can be seen that it easily remains in the eye.

Comparative Example 6 (When M./M, I of hydroxypropyl methylcellulose is large) Methoxy group content 28.9%, hydroxypropoxy group content 10.5%, weight average obtained by blending two types of hydroxypropyl methylcellulose. Molecular weight 56
0000. Hydroxypropyl methyl cellulose with M, /M, = 6°2 was dissolved in T4 saline to prepare a 2.0% solution. The resulting solution was filtered three times through a 0.8 μm membrane filter. The viscosity at 20°C is 14
It was 7QQcps. It was injected into the eyes of rabbits in the same manner as in Examples 3 and 4, and the intraocular pressure was measured.
Intraocular pressure increased from 3nmHg to 47mnHg. This intraocular pressure returned to almost its original state after 24 hours.

Comparative Example 1 (Hydroxypropylmethylcellulose without hydroxypropoxy group) Methoxy group content 31.2%, weight average molecular weight 5aoooo, Mw /M
N-4,4 methyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in physiological saline to prepare a 1.8% solution. solution 2
The viscosity at 0°C was 10,400 cps. This solution was filtered through a 0°8 μm membrane filter at a rate of 3 kg/
When filtration was carried out under a constant pressure of cm2, as shown in FIG. 3, the filtration performance did not improve at all even if the number of filtration times was increased, and clogging occurred with a small amount of filtration.

Comparative Example 8 When the filtrate of Comparative Example 7 was injected into the anterior chamber of a rabbit eye in the same manner as in Example 3, inflammation occurred after 24 hours and did not recover even after 48 hours.

[Brief explanation of the drawings] Figure 1 shows the amount of filtration at each number of filtration times when the hydroxypropyl methylcellulose solution prepared in Example 2 was filtered with a 0.8 μm membrane filter at a constant pressure of 3 kg/11 g of Cl. It is a graph showing the relationship between the flow rate and the flow velocity. Figure 2 shows the relationship between filtration amount and flow rate at each filtration number when the hydroxypropyl methylcellulose solution prepared in Comparative Example 3 was filtered with a 0.8μ membrane filter at a constant pressure of 3kg/cm. Fig. 3 shows the methyl cellulose solution prepared in Comparative Example 7 filtered through a 0.8 μm membrane filter at 3 kg/c++.
It is a graph showing the relationship between the filtration amount and the flow rate at each number of filtration times when filtration is performed at a constant pressure of ``.

Claims (2)

[Claims] (1) Methoxy group content 28-32%, hydroxypropoxy group content 7-12%, weight average molecular weight (M_W) 4
Hydroxypropyl methyl cellulose with a ratio of weight average molecular weight to number average molecular weight (M_N) (M_W/M_N) of 20,000 to 800,000 and 5.5 or less, within the concentration range defined by the following formula, natural logarithm of maximum concentration: logC_M_A_X = 0.64 -0.0055M Natural logarithm of the minimum concentration: logC_M_I_N=0.57-0.0071M (where, C_M_A_X is the maximum concentration (%) of hydroxypropyl methylcellulose, C_M_I_N is the minimum concentration (%) of hydroxypropyl methylcellulose, and M is hydroxypropyl A viscoelastic solution for ophthalmic surgery dissolved in water containing salts so that the weight average molecular weight of methylcellulose is x 10^-^4. (2) When the solution concentration of hydroxypropyl methyl cellulose is approximately 0.02%, the number of fine particles of 2 μm or more measured by electrical resistance method is 2500 particles/ml or less, and the number of fine particles of 4 μm or more is 20 particles/ml or less. A viscoelastic solution for ophthalmic surgery according to claim 1.