JP2003192583A - Antiinflammatory eye drop - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antiinflammatory eye drop excellent in abirritant action on eyes based on dichlofenac sodium which is a main medicine ingredient and excellent in storage stability to light and heat. <P>SOLUTION: This antiinflammatory eye drop comprises an aqueous solution obtained by preparing a formulation obtained by adding chlorobutanol and a polyvinylpyrrolidone to dichlofenac sodium as a main medicine ingredient with one or more kinds of compounds selected from benzyl alcohol, glycerol, edetate sodium, creatinine and sodium thiosulfate and one or more substances selected from polyethylene glycols and nonionic surfactants. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an anti-inflammatory eye drop containing sodium diclofenac as a main ingredient. More specifically, the present invention relates to an eye drop which is excellent in storage stability of the main drug component as well as alleviating eye irritation based on the main drug component.

[0002]

2. Description of the Related Art Conventionally, Diclofenac sodium (monoso-dium 2- (2,6-dic
There is an anti-inflammatory eye drop containing hloroanilino) phenylacetate) (Patent No. 3155689 etc.).

Although diclofenac sodium is useful as a local therapeutic agent for eye inflammation, it is known to have the drawback of having irritation to the eye. For this reason, conventional eye drops containing diclofenac sodium as a main ingredient have a formulation in which chlorobutanol is used as an irritation-relieving agent because of its good compatibility with the main ingredient.

In this conventional eye drop formulation, chlorobutanol is stable under acidic conditions but unstable under neutral or alkaline conditions and decomposes to cause a drop in pH, resulting in discoloration of the solution to yellowish brown. It has been considered that it is not suitable as an eye drop to be used in a neutral or alkaline manner, since it will increase irritation to.

Conventionally, a composition using a soothing agent such as acidic mucopolysaccharide in addition to chlorobutanol has been developed as a stimulant alleviating agent (Japanese Patent No. 3155689).

Diclofenac sodium itself, which is the main drug component, is particularly inferior in stability to light and heat. Therefore, in order to ensure the stability of the aqueous solution during storage, it is necessary to be in a light-shielded state, and the storage temperature is regulated to be kept at 10 ° C. or lower. Patent No. 31556 mentioned above
The formulation of Invention No. 89 makes no mention of the stability of this active ingredient.

Regarding eye drops containing diclofenac sodium as a main ingredient, benzalkonium chloride and cetylpyridinium chloride are commonly used as conventional compositions for stabilizing the main ingredient, but these stabilizers are It has the disadvantage of poor compatibility with diclofenac sodium. Therefore, 2-amino-2-hydroxymethyl-1,3-2-propanediol (trometamol)
Alternatively, a composition in which a homologue within a certain range is blended has been proposed (Japanese Patent No. 2515788).

[0008]

However, in the eye drops containing the above-mentioned conventional stimulant-relieving agent, sufficient stability of the main drug component against light and heat cannot be obtained, and still the stimulus to the eye is alleviated. Is insufficient. Moreover, the above-mentioned conventional eye drops containing trometamol or a homologue within a certain range thereof do not sufficiently relieve irritation to the eyes.

Therefore, an object of the present invention is to provide an anti-inflammatory eye drop based on the main ingredient, diclofenac sodium, which is excellent in the action of relieving irritation to the eye and at the same time excellent in storage stability against light and heat.

[0010]

In order to achieve the above-mentioned object, the anti-inflammatory eye drops of the present invention comprises diclofenac sodium as a main ingredient and a formulation in which chlorobutanol and polyvinylpyrrolidones are added to benzyl alcohol, It is characterized by comprising an aqueous solution containing one or more selected from glycerin, sodium edetate, creatinine and sodium thiosulfate, and one or more selected from polyethylene glycols and nonionic surfactants. And

In the anti-inflammatory eye drops of the present invention described above, diclofenac sodium is a non-steroidal analgesic and anti-inflammatory drug listed in the 13th revised Japanese Pharmacopoeia and used for preventing postoperative inflammation of the eye. .

The amount of diclofenac sodium as the main ingredient is preferably 0.01 to 1.0% by weight, more preferably 0.1 to 0.5% by weight.
If the content of diclofenac sodium is less than 0.01% by weight, it may be difficult for some people to effectively prevent the inflammation of the eye, and if it exceeds 1.0% by weight, solubilization is difficult. , It becomes difficult for a person to endure the stimulating action when instilled.

Chlorobutanol is listed in the Japanese Pharmacopoeia and is a pharmaceutical additive that acts as a buffer, a preservative, a preservative, and a soothing agent. The action of chlorobutanol is known to have a local anesthetic action, and the action can reduce eye irritation immediately after instillation. Therefore, a formulation that does not contain chlorobutanol cannot sufficiently supplement the palliative action against eye irritation, and it is necessary that chlorobutanol be an essential component in the eye drops containing the main drug component.

The content of chlorobutanol as the above-mentioned stimulant is preferably 0.1 to 0.7% by weight, more preferably 0.3 to 0.5% by weight. If the content of chlorobutanol is less than 0.1% by weight, the soothing and antiseptic effects are lost,
If it exceeds 0.7% by weight, insolubilization occurs.

As other stimulants, magnesium chloride, trimetamol, epsilon-aminocaproic acid, etc. can be used together with chlorobutanol. As a result, the effect of synergistically reducing the irritation to the eyes can be exhibited.

Polyvinylpyrrolidones are blended as a dispersant. Polyvinylpyrrolidones include k25 having an average molecular weight of about 25,000 and k3 having an average molecular weight of about 40,000.
A generally used one such as 0 and k90 having an average molecular weight of about 120,000 is suitable.

The blending amount of polyvinylpyrrolidones is 2.
It is 0 to 8.0% by weight. If less than 2.0% by weight,
The main drug component may become insoluble in some cases, and if it exceeds 8.0% by weight, the solution may be dried and gelatinized due to its high viscosity.

One or more selected from benzyl alcohol, glycerin, sodium edetate, creatinine and sodium thiosulfate act as a stabilizer for the main drug component. Benzyl alcohol is particularly preferable because it is preferable for the stimulant relaxing action on the main drug component and is excellent in stability and antiseptic effect.

The amount of stabilizer added is 0.05 to 5% by weight.
Is preferable, and more preferably 0.1-1.
It is 0% by weight. In this quantitative range, there is an effect of stabilizing the main drug component against chemical decomposition and stabilizing the preservative against decomposition in an aqueous solution. If the compounding amount of the stabilizer is less than 0.05% by weight, the stabilization of the active ingredient will be insufficient. As with sodium thiosulfate, sodium bisulfite and sodium sulfite can also be used.

Polyethylene glycol (macrogol,
The PEGs) and the nonionic surfactant exert a stimulus alleviation effect and a stabilizing effect on the main ingredient, in particular. Polyethylene glycols include various polyethylene glycols, preferably Macrogol 400 listed in the Japanese Pharmacopoeia,
1500, 4000, 6000 and 20000. Nonionic surfactants include polyoxyethylene hydrogenated castor oil, glyceryl monostearate, polysorbates, and the like.

The content of polyethylene glycols and nonionic surfactant is preferably 0.01 to 3% by weight.
Range, more preferably 0.05 to 1.0% by weight
Is.

The eye drop of the present invention preferably has a pH of 5.5.
To 7.5, more preferably pH 6.0 to 7.0, and examples of the pH buffering agent include boric acid, borax, phosphate, and organic acid. The buffer may be blended by one kind or a combination of two kinds. In the eye drop of the present invention, for example, the pH value is buffered by the presence of boric acid or borax, or citrate, and the addition of one or more of creatinine and sodium thiosulfate stabilizes chlorobutanol. , Its decomposition is prevented. As a result, it is possible to eliminate the above-mentioned adverse effects due to the decomposition of chlorobutanol.

The method for producing the eye drop of the present invention may be a known method. For example, at room temperature, polyvinylpyrrolidones are dissolved in sterilized purified water using a high-speed stirrer, and then chlorobutanol, a stabilizer, and a solubilizing agent are added and dissolved in this order. Then, the remaining amount of sterile purified water is added to obtain the eye drop of the present invention. Furthermore, by adding boric acid, borax and the like, it is possible to adjust the preferable pH of the eye drop to 6.0 to 7.5 and the osmotic pressure ratio with physiological saline to 0.9 to 1.1.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION (Test Examples 1 to 8)

[0025]

[Table 1]

With the compounding ratio shown in Table 1, the total amount of 8
Polyvinylpyrrolidone K in 0% by weight of sterile purified water
25 (hereinafter referred to as PVP.K25) was added and dissolved using a high-speed stirrer (Ultra Tarax, 7400 rpm), and then boric acid, borax, and polysorbate 80 were added and dissolved. A sample of Test Example 1 was obtained by adding the remaining amount of sterile purified water to this. In addition, in Test Examples 2 to 7,
Glycerin, mannitol, P
Any one of EG4000, D-sorbitol, EDTA-2Na, and benzalkonium chloride was added and dissolved, and then the remaining amount of sterile purified water was added thereto to obtain each sample. Moreover, by adding boric acid or borax, the pH of 5.5 to 7.5 and the osmotic pressure ratio are set to 0.9.
Adjusted to ~ 1.1. In addition, each of the above-mentioned samples is made of polypropylene having a capacity of 5 mL (hereinafter, simply referred to as “P
P ”. ) (White transparency, cylindrical shape) was filled and used for the next test. In addition, Test Example 8 is a commercial product of another company (“Wakamito Pharmaceutical Co., Ltd.'s“ Dicroad Eye Drop ”, Lot
OX39) was similarly filled into a PP container. For the prescription, refer to Vol.

Each sample was subjected to a light irradiation test at 25 ° C. and an accelerated test at 40 ° C., and the content immediately after the production of the main ingredient was converted to 100%. The results are shown in Table 2.

[0028]

[Table 2]

In Table 2, the method of quantifying diclofenac sodium as the main ingredient was as follows. That is, a volume corresponding to 2 mg of diclofenac sodium is accurately measured, 10 mL of an internal standard solution (n-hexyl parabenzoate in methanol) is accurately added thereto, and water is added to make 20 mL, which is used as a sample solution. Separately, diclofenac sodium standard product is dried at 105 ° C. for 3 hours, and about 0.05 g thereof is precisely weighed, and water is added to dissolve it to make exactly 100 mL. In addition, diclofenac sodium standard product is 70-75 in dichlorofenac sodium 10 g in Japanese Pharmacopoeia in 5% acetone aqueous solution 50 mL.
Melt at ℃. To this, 1.5 g of activated carbon is added, and decolorizing filtration is performed while hot. The crystals were washed twice with 1 mL of purified water, and recrystallized again by the same method as above to obtain 65 to 7
It is obtained by drying at 5 ° C. Measure exactly 4 mL, add exactly 10 mL of the internal standard solution, add water and add 20 mL.
Make up mL and use this as the standard solution.

[0030] For the sample solution and standard solution 20 [mu] L, under the following conditions was tested by liquid chromatography to determine the ratio Q _T and Q _S of diclofenac peak area to the peak area of internal standard. These values are applied to the following equation to obtain the amount (mg) of diclofenac sodium with respect to the sampling volume.

Amount (mg) of diclofenac sodium relative to the sampling volume = Amount (mg) of diclofenac sodium standard product × Q _T / Q _S × 1/25 From the results of Table 2, when mannitol of Test Example 3 was blended, It can be seen that it is difficult to stabilize the main drug component in the eye drop by light and heat and when D-sorbitol of Test Example 5 is blended.

On the other hand, in the light irradiation test and the acceleration test, in the case of the compounded compositions of Test Examples 1, 2, 4, 6 and 7, the same stability as that of the commercially available product of Test Example 8 is shown. . In addition, when benzalkonium chloride of Test Example 7 is blended, it is difficult to blend it because it has a drawback that it has poor compatibility with diclofenac sodium as described above.

Next, the APH relating to the change in the coloring degree of the solution
An A (American Public Healthy Asso-ciation) measurement test was performed in a light irradiation test and an acceleration test, and the results are shown in Table 3.

[0034]

[Table 3]

The APHA measurement method is described in JOCS 3.2.
According to 1.2-1996, "Standard method for analyzing fats and oils", the absorbance of the sample at a wavelength λ = 450 nm was measured and determined by the least square method by the following formula. APHA = absorbance / 0.
From the results of Table 3, from the results of Table 3, in the case of the compounded compositions of Test Examples 6 and 7, the coloring suppression effect by the light irradiation test is large, and in the composition of the commercial product of Test Example 8, the coloring degree in the severe test is large. I understand.

From the results of these tests, the stabilizer is
It can be seen that it is preferable to blend glycerin of Test Examples 2, 4 and 6, PEG4000 and EDTA-2Na (sodium edetate).

(Test Examples 9 to 12) Next, the composition containing glycerin was tested for its effect on monobasic sodium phosphate, dibasic sodium phosphate and sodium citrate.

[0038]

[Table 4]

Samples of Test Examples 9 to 12 were prepared with the compounding ratios shown in Table 4 in the same manner as in Test Example 1 above.
Each sample was filled in the same PP container as in the test example and subjected to the next test. In Test Examples 9 and 10, when the first and second sodium phosphates were added to the basic composition and when glycerin was added to these, Test Examples 11 and 12 were
There are a case where sodium citrate is added to the basic composition and a case where glycerin is added to this.

Each sample was subjected to the same light irradiation test and acceleration test as described above, and the content of the main component immediately after its production was 100.
%, And the result is shown in Table 5.

[0041]

[Table 5]

Further, an APHA measurement test was conducted under light irradiation and acceleration conditions at 40 ° C., and the results are shown in Table 6.

[0043]

[Table 6]

In Table 5, the method of quantifying diclofenac sodium, which is the main drug component, and in Table 6, APHA
The measuring method was the same as the above.

From the results shown in Table 5 and Table 6, Test Example 9
Compared with the same as the above, there is almost no difference in the remaining amount of the active ingredient in the light irradiation test and the acceleration test, but APHA
Regarding the value, it can be seen that Test Example 10 has a large coloring suppressing effect. That is, the effectiveness of blending glycerin is recognized. Further, similarly, the same as in Test Example 11
Also in comparison with 2, particularly in Test Example 12,
It can be seen that the stability in the light irradiation test is high, and the APHA value has a large effect of suppressing coloring. Therefore, it can be seen that the combination of glycerin is effective. Therefore, the basic composition, in the composition of the first and second sodium phosphate, or sodium citrate, in any case, the addition of glycerin is effective against light and heat, An improvement in stability and an effect of suppressing coloring are expected. Moreover, it can be seen that, in the buffer, sodium phosphate has a larger effect of suppressing coloring than sodium citrate.

(Test Examples 13 to 18) Next, in particular, EDT
The composition containing A-2Na and glycerin was tested for the effect of the addition of other components.

[0047]

[Table 7]

Samples of Test Examples 13 to 18 were prepared in the same proportion as shown in Table 7 by the same method as in Test Example 1 above.
For Test Examples 13 and 14, methylparaben and propylparaben were mixed as preservatives, for Test Examples 15 and 16, sorbic acid was mixed, and Test Examples 13 to 1 were used.
For No. 6, HCO60 (polyoxyethylene hydrogenated castor oil) or polysorbate 80 was blended as a surfactant. In Test Examples 17 and 18, boric acid and trometamol or boric acid and borax were blended as a buffer.
Test Example 17 contains EDTA-2Na and does not contain glycerin. Test Example 18 is a commercial product of the same other company as Test Example 8 and does not contain EDTA-2Na and glycerin. Each sample was filled in the same PP container as the sample of Test Example 1 and subjected to the next test.

For each sample, a light irradiation test similar to the above,
An accelerated test and a severe test were conducted, and the content of the main ingredient immediately after production was converted to 100% and the results are shown in Table 8.

[0050]

[Table 8]

In Table 8, the method for quantifying diclofenac sodium as the main ingredient was the same as the above.

From the results shown in Table 8, Test Examples 13 to 18
In the light irradiation test, the samples of
Except for, the decrease of the main drug component is about the same, and in the accelerated test by heat, all the main drug components are stable at about the same level, but under severe heat conditions, EDTA-
The commercial product of Test Example 18, which does not contain 2Na and glycerin, is extremely unstable. Therefore, it can be seen that EDTA-2Na and glycerin act stably against heat. It can also be seen that the other components have almost no effect in the severe test.

In addition, under the conditions of light irradiation, acceleration and severeness, A
Each PHA measurement test was conducted, and the results are shown in Table 9.

[0054]

[Table 9]

In Table 9, the APHA measurement test was carried out in the same manner as described above.

From the results shown in Table 9, regarding the effect of suppressing coloring, in the light irradiation test, Test Example 13 and then Test Example 1 were used.
4, 17 and 18 are equally good, and for thermal acceleration, Test Example 17 is valid, followed by Test Examples 13 and 14. However, in the case of the commercially available product of Test Example 18 (“Dixroad ophthalmic solution” manufactured by Wakamoto Pharmaceutical Co., Ltd., Lot OX39), the solution was extremely colored. Therefore, test example 1
It can be seen that in the formulations of 3, 14 and 17, even after 8 weeks of acceleration, almost no decrease in the active ingredient was observed and the effect of suppressing coloration was very high.

That is, from Test Examples 15 and 16, when sorbic acid is added, the solution is greatly colored by light and heat. In addition, from Test Example 17, the addition of trometamol enhances the coloration suppressing effect, and from the comparison between Test Example 14 and Test Examples 17 and 18, boric acid and borax are stable in the main drug component and in solution. It can be seen that it does not affect coloring.

[0058]

Examples (Comparative Examples 1 to 5)

[0059]

[Table 10]

Polysorbate 80 was added to 80% by weight of total sterilized purified water at room temperature at the compounding ingredients shown in Table 10 and their proportions, and this was added using a high-speed rotary stirrer (Ultra Turrax, 7400 rpm). After dissolving
Sorbic acid, boric acid, trometamol, and EDTA-
2Na was added and dissolved in this order. Diclofenac sodium was added to this solution, and the mixture was stirred and dissolved, and then the remaining amount of sterile purified water was added to bring the total volume to 500 mL. This aqueous solution was filtered through a membrane filter having a pore size of 0.22 μm, and then the aqueous solution was filled in a polypropylene container (white transparency, cylindrical shape) having a capacity of 5 mL, which was used for Comparative Example 1.
Of the sample. The samples of Comparative Examples 2 and 3 were similarly prepared.

The irritation relaxation properties shown in Table 10 are shown by the average value of the evaluation by the method of the sensory test when instilled by 3 healthy persons. The evaluation of the stimulus relaxation property is represented by sensory points of 0 to 5, where 0 is extremely good when there is no stimulus, 2 is an instant sensation of stimulus, and 3 is a sensation of continuous stimulus. , Slightly bad, 4 was when there was a fairly strong irritation, and 5 was when I felt an unbearable irritation.

Table 11 shows the residual amount (%) of the main component in the light irradiation test, the acceleration test and the severe test, and the APHA measurement result of each sample of Comparative Examples 1 to 3 together with the change in pH value. It was

[0063]

[Table 11]

In Table 11, the method for quantifying diclofenac sodium as the main ingredient and the method for measuring APHA were the same as those described above.

From the results shown in Tables 10 and 11, the samples of Comparative Examples 1 to 3 are relatively stable under light irradiation, but with respect to the stimulus relaxation property, irritation is felt when instilled. A large value of 1.0 or more was shown.

Therefore, with respect to the irritation relieving property of the eye drops,
It turns out that the blending of chlorobutanol is essential,
As described above, it has been recognized that it is necessary to devise a method for improving coloration and a decrease in pH value due to decomposition by heat or light, which is a drawback in the formulation of chlorobutanol.

For this reason, Comparative Example 4 was prepared with chlorobutanol as a compounding ingredient. Further, the commercially available product of Comparative Example 5 (Wakamoto Pharmaceutical Co., Ltd. “Dicroad Eye Drop”, Lot OX39) also contains chlorobutanol as a blending component, but as shown in Table 10,
Although the stimulus relaxation property is reduced, as shown in Table 11, it can be seen that the stability of the main component under light irradiation, acceleration and severe conditions cannot be ensured.

(Examples 1 to 5)

[0069]

[Table 12]

Next, at the mixing ratio shown in Table 12, at room temperature,
PVP / K25 and polyoxyethylene hydrogenated castor oil were added and dissolved in 80% by weight of sterilized purified water using a high-speed rotary stirrer (Ultra Turrax, 7400 rpm), and then benzyl alcohol, chlorobutanol, glycerin, and boron were added. Acid, borax, EDTA-2Na and creatinine were added and dissolved in this order. Diclofenac sodium was added to this solution, and the mixture was stirred and dissolved, and then the remaining amount of sterile purified water was added to bring the total volume to 500 mL. This aqueous solution was filtered through a membrane filter having a pore size of 0.22 μm, and then the aqueous solution was filled into a polypropylene container (white transparency, cylindrical shape) having a volume of 5 mL, which was used as a sample of Example 1. At this time, the solubility of the active ingredient was good in all the samples. Example 2
The samples of Nos. 5 to 5 are almost the same as those of the comparative example except for the difference in the blending components. The evaluation criteria of the sensory test in Table 12 are the same as those in the comparative example described above.

From the results shown in Table 12, the samples of Examples 1 to 5 had a stimulus relaxation property of 0.
It was a small value of less than 5, and both were good or better.

Table 13 shows the residual amount (%) of the main ingredient in the light irradiation test, the acceleration test and the severe test and the APHA measurement result of each sample of Examples 1 to 5 together with the change in pH value. It was

[0073]

[Table 13]

In Table 13, the method for quantifying diclofenac sodium, which is the main ingredient, and the method for measuring APHA were the same as those described above.

From the results shown in Tables 12 and 13, the samples of Examples 1 to 5 exhibited a considerable relaxation effect with respect to non-stimulation and a decrease in pH value as compared with the comparative example. However, it is found that the main drug component is stable by light and heat, the APHA measurement value is low, and the degree of color modification is low.

That is, the formulation of the eye drop containing chlorobutanol can be made non-irritating and stable by adding creatinine or sodium thiosulfate.

[0077]

Since the present invention is constructed as described above, the following effects are exhibited. In the composition of the anti-inflammatory eye drops of the present invention, chlorobutanol and polyvinylpyrrolidone are added to the main drug component under stable conditions, so that the composition is excellent in irritation relaxation and each component containing diclofenac sodium, which is the main drug component. It is now possible to maintain a stable state under accelerated and severe conditions.

By adjusting the pH value to 5.5 to 7.5, it is possible to obtain an eye drop which is excellent in stability by light and heat and is excellent in non-irritancy as an eye drop.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/22 A61K 47/22 47/32 47/32 47/34 47/34 A61P 27/02 A61P 27 / 02 29/00 29/00 F-term (reference) 4C076 AA12 BB24 CC05 CC10 DD07A DD22 DD29 DD37A DD49A DD55A DD60A EE16A EE23A FF61 FF63 FF67 4C206 AA01 AA02 DB22 KA01 MA03 MA33 MA11 MA14 MA29 MA37 MA11 NA14 ZA33

Claims (2)

[Claims] 1. Diclofenac sodium as a main drug component, and chlorobutanol and polyvinylpyrrolidone added to the formulation, and one or two kinds selected from benzyl alcohol, glycerin, sodium edetate, creatinine and sodium thiosulfate. 1 selected from polyethylene glycols and nonionic surfactants
An anti-inflammatory eye drop comprising an aqueous solution containing at least one species. 2. The anti-inflammatory eye drop preparation according to claim 1, wherein the pH is adjusted to 5.5 to 7.5 by adding a buffering agent.