JP2741285B2 - Glaucoma treatment - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a pharmaceutical composition for treating glaucoma, which has no side effects, is stable and has an excellent intraocular pressure lowering action at a low concentration. Background Art Glaucoma is an intraocular pressure (intraocular pressure) of the eyeball. Due to abnormally high, the eyes are easily tired, and the eyes are blurred or hurt, and various symptoms such as weakened vision become apparent,
It is a risk of blindness. When you get this disease,
The eyeball becomes hard like a stone, and the back of the pupil (pupil) looks blue.

In the eyeball, a liquid such as water (aqueous humor) constantly circulates to maintain a constant intraocular pressure (intraocular pressure = 15 to 20 mmHg).
It is regulated by the circulation of blood and lymph, the elasticity of the eyeball wall, and the function of the nerves that control it. Modulation of any of these causes an increase in intraocular pressure and glaucoma.

If the modulation is due to eye diseases such as iritis, trauma or vitreous hemorrhage, it is called secondary glaucoma. However, glaucoma, which is usually a problem, is primary glaucoma where the cause of the modulation is unknown.

Primary glaucoma is (1) acute glaucomatous inflammatory glaucoma,
There are three types: (2) simple glaucoma that progresses chronically and (3) congenital glaucoma.

2. Description of the Related Art Conventionally, various drugs have been used for the purpose of preventing glaucoma or reducing elevated intraocular pressure for treating glaucoma. As an intraocular pressure reducing agent, for example, sympathomimetics such as epinephrine are known.However, epinephrine, when used for narrow-angle glaucoma due to mydriatic action, intensifies the angle occlusion and causes an acute increase in intraocular pressure. Not only can it occur, but also elevated blood pressure and conjunctival pigmentation are common.

In addition, a parasympathomimetic such as pilocarpine causes darkness in the visual field or dysregulation due to miosis.

Furthermore, recently, β-adrenergic blockers such as timolol have been widely used for the treatment of glaucoma due to their effect of inhibiting aqueous humor production (Drug The rapy Practical Series Pharmacotherapy for glaucoma, 70 to 75 Page, 1
(990), since β-adrenergic blockers have been reported as systemic side effects such as bradycardia, heart failure and asthma attack, they cannot be used for patients with such symptoms.

In addition, it has been suggested that α ₁ -adrenergic blockers have an effect of promoting aqueous humor outflow, suggesting that bunazosin hydrochloride may be a new therapeutic agent for hypotensive glaucoma by increasing choroidal blood flow. (Journal of the Japanese Ophthalmology, Vol. 42, pp. 710-714, 1991). Therefore, it may be used for the treatment of glaucoma, but it is inevitable that conjunctival hyperemia and miosis occur due to the vasodilatory action.

On the other hand, a β-adrenergic stimulant is expected to be used for such patients, but a conventional β-adrenergic stimulant such as sultamol cannot exert a sufficient effect unless the concentration is high. Therefore, it is said that repeated use is impossible because conjunctival congestion occurs markedly.

As described above, at present, a satisfactory pharmaceutical composition for treating glaucoma, which has few side effects as described above and is effective at a stable and low concentration, has not yet been found.

By the way, recently, 5- {1-hydroxy-2- [2-
(2-methoxyphenoxy) ethylamino] ethyl}-
A phenylethanolamine derivative containing 2-methylbenzenesulfonamide hydrochloride (hereinafter, referred to as amoslarol hydrochloride) or a salt thereof has both an α-adrenergic blocking action and a β-adrenaline blocking action, and is a blood pressure lowering agent or angina. It has been reported that it is effective as an agent for treating symptom (JP-A-54-95544).

In addition, the above compound having both an α-adrenergic blocking action and a β-adrenergic blocking action is represented by α- and β-adrenergic blocking action.
-It is useful as an active ingredient such as an α / β blocker, specifically, an antihypertensive agent, an antianginal agent, an antiarrhythmic agent, etc., as an agent for improving the disadvantages of side effects associated with the combined use of a blocker. (Japanese Patent Application Laid-Open No. 55-73610).

In view of this situation, the present inventors have found that the above-mentioned drugs do not have the drawbacks (side effects) of the above-mentioned conventional drugs, and have both the mechanism of action of inhibiting aqueous humor production and promoting the outflow of aqueous humor. As a result, intensive research was conducted to find a drug having an effective intraocular pressure lowering action at a low concentration. As a result, the present inventors have found that amosulalol hydrochloride described in the above publication has a surprisingly unexpected excellent excellent intraocular pressure lowering action, has few side effects observed with conventional drugs, and is stable and low. It was found that the composition was effective at a concentration, and the present invention was completed.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition for treating glaucoma, which is free from the above-mentioned drawbacks (side effects), has a stable and effective intraocular pressure lowering effect at a low concentration.

That is, the present invention uses the formula 5- {1-hydroxy-2- [2- (2-methoxyphenoxy) ethylamino] ethyl} -2-methylbenzenesulfonamide (hereinafter referred to as amosulalol) represented by the following formula or an acid salt thereof as an active ingredient: The present invention relates to a novel and useful pharmaceutical composition for treating glaucoma and a pharmaceutical composition for reducing intraocular pressure. Examples of the acid salt include an inorganic acid salt such as a hydrochloride and a sulfate, and an organic acid salt such as a maleate, a tartrate and a citrate, and a hydrochloride (ie, amosulalol hydrochloride) is preferable.

The physicochemical properties of amosulalol or an acid salt thereof as an active ingredient of the pharmaceutical composition for treating glaucoma of the present invention and a method for producing the same are described, for example, in the above-mentioned JP-A-54-95544.

As is clear from the test examples described below, the pharmaceutical composition for treating glaucoma of the present invention has an excellent intraocular pressure-lowering effect at a low concentration, and has low toxicity and is stable, and thus is effective for treating various glaucoma. It can be used as an important drug.

When amosulalol or an acid salt thereof is used as a pharmaceutical composition for treating glaucoma, it is usually mixed with a known pharmacologically acceptable carrier, excipient, diluent, etc., and according to a known method, for example, eye drops Or parenteral preparations such as eye ointments and injections, or oral preparations such as tablets, capsules and granules.

For example, when the pharmaceutical composition for treating glaucoma of the present invention is used as an eye drop, a buffer, an isotonic agent, a preservative, a solubilizing agent, which is usually added to the eye drop, as long as the purpose of the present invention is not impaired. Additives such as a stabilizer, a pH adjuster, a thickener, and a chelating agent may be appropriately added.

Among the above additives, examples of the buffer include a phosphate buffer, a borate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, an amino acid and the like.

Examples of the tonicity agent include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin, polyethylene glycol, and propylene glycol; and salts such as sodium chloride.

Examples of the preservative include benzalkonium chloride, benzethonium chloride, paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or a salt thereof, thimerosal chloroptanol and the like. Can be

Examples of the solubilizer (stabilizer) include cyclodextrins and derivatives thereof, water-soluble polymers such as polyvinylpyrrolidone, and surfactants.
It is preferable to use polyvinylpyrrolidone or cyclodextrin. For example, in the formulation of 0.5% amosulalol hydrochloride eye drops, 0.01-2.0% polyvinylpyrrolidone is added as a stabilizer.

Examples of the pH adjuster include hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, and ammonium hydroxide.

Examples of the thickener include hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof.

Examples of the chelating agent include sodium edetate,
Examples include sodium citrate and condensed sodium phosphate.

When the pharmaceutical composition for treating glaucoma of the present invention is used as an ophthalmic ointment, purified lanolin, vaseline, plastibase, liquid paraffin, polyethylene glycol and the like are appropriately used as the ointment base.

Furthermore, the pharmaceutical composition for treating glaucoma of the present invention comprises a tablet,
It can also be used as an oral preparation such as capsules and granules, or as an injection.

The dosage of the pharmaceutical composition for treating glaucoma of the present invention varies depending on the administration route, symptoms, age and weight of the patient. For example, when used as an eye drop for adult glaucoma patients, the active ingredient, amosulalol, is used. Or about 0.001 to 5.0% w / v, preferably about 0.05 to 1.0% w / v
As an ophthalmic solution containing about v%, one dose 1 depending on symptoms
It is desirable to administer ~ several drops one to four times a day.

When the pharmaceutical composition for treating glaucoma of the present invention is used as an ophthalmic ointment, the ophthalmic ointment containing the active ingredient in an amount of about 0.001 to 10 w / w%, preferably about 0.05 to 1.0 w / w%, has It is desirable to administer about 1 to 4 times a day accordingly.

One or more other pharmaceutical compositions for treating glaucoma may be added to the pharmaceutical composition for treating glaucoma of the present invention as long as the object of the present invention is not violated.

In addition, the pharmaceutical composition for treating glaucoma of the present invention may appropriately contain, in addition to the above-mentioned pharmaceutical composition for treating glaucoma, other components having a medicinal effect, as long as the object of the present invention is not contravened.

Another embodiment of the present invention includes a composition for treating glaucoma, comprising amoslarol hydrochloride and polyvinylpyrrolidone or α-cyclodextrin. Amosulalol hydrochloride is stable to heat and light in the form of an aqueous solution, but when the solution freezes upon cooling and returns to room temperature,
Crystals formed during freezing may not thaw. Therefore, if it was frozen during storage in a cold place, it was considered that there was a problem in subsequent use.

The present inventors have searched for a pharmaceutical composition that does not have the above-described problems, and as a result, have found that when polyvinylpyrrolidone or α-cyclodextrin is added to an aqueous solution of amosulalol, the composition can be used without remaining crystals.

In this embodiment as well, additives such as the above-mentioned buffers, isotonic agents, preservatives, pH adjusters, thickeners, chelating agents and the like may be added as desired, as long as the object of the present invention is not impaired.

Hereinafter, the present invention will be described in more detail with reference to Examples, and the effects of the present invention will be clarified by Test Examples. However, this is merely an example, and the scope of the present invention is not limited thereto. Absent.

EXAMPLES [Example 1] Eye drops An eye drop was prepared according to the following formulation.

Amosulalol hydrochloride 0.05 g Mannitol 5.0 g Sodium dihydrogen phosphate 0.1 g Methyl parahydroxybenzoate 0.02 g Propyl parahydroxybenzoate 0.01 g Dilute hydrochloric acid qs (pH 6.0) Add sterilized purified water to make up to 100 ml in total volume.

[Example 2] Eye drops An eye drop was prepared according to the following formulation.

Amosulalol hydrochloride 0.1 g Boric acid 2.0 g Benzalkonium chloride 0.005 g Sodium hydroxide Appropriate amount (pH 6.0) Add sterilized purified water to make the total volume 100 ml.

[Example 3] Eye drops An eye drop was prepared according to the following formulation.

Amosulalol hydrochloride 0.25 g Concentrated glycerin 2.6 g Sodium acetate 0.1 g α-Cyclodextrin 0.1 g Methyl parahydroxybenzoate 0.02 g Bropyl paraoxybenzoate 0.01 g Dilute hydrochloric acid qs (pH 4.5) Add sterilized purified water to make a total volume of 100 ml.

[Example 4] Eye drops An eye drop was prepared according to the following formulation.

Amoslarol hydrochloride 0.5 g Condensed glycerin 2.6 g Sodium acetate 0.1 g Benzalkonium chloride 0.005 g Dilute hydrochloric acid qs (pH 5.0) Add sterile purified water to make up to 100 ml in total volume.

[Example 5] Eye drops An eye drop was prepared according to the following formulation.

Amoslarol hydrochloride 0.5 g Concentrated glycerin 2.6 g Sodium acetate 0.1 g Polyvinylpyrrolidone 0.5 g Benzalkonium chloride 0.005 g Dilute hydrochloric acid qs (pH 5.5) Add sterilized purified water to make a total volume of 100 ml.

[Example 6] Eye drops An eye drop was prepared according to the following formulation.

Amoslarol hydrochloride 1.0 g Concentrated glycerin 2.6 g Sodium monohydrogen phosphate 0.1 g Polyvinyl pyrrolidone 1.0 g Sodium edetate 0.05 g Benzalkonium chloride 0.005 g Sodium hydroxide Appropriate amount (pH 4.0) Add sterilized purified water to make up to 100 ml in total volume .

Example 7 Eye Ointment An eye ointment was prepared according to the following formulation.

Amosulalol hydrochloride 1.0 g Liquid paraffin 1.0 g White petrolatum qs 100 g [Example 8] Eye ointment An eye ointment was prepared according to the following formulation.

Amosulalol hydrochloride 0.5 g Liquid paraffin 1.0 g White petrolatum qs 100 g Test example [Test example 1] Intraocular pressure-lowering effect of amosulalol hydrochloride on normal intraocular pressure of colored rabbits After confirming that there is no abnormality in the eyes, temperature 24 ± 4
They were bred in a breeding room at a temperature of 55 ° C. and a humidity of 55 ± 15%, and fed a solid feed [Lab RG-RO, Nippon Nosan Kogyo Co., Ltd.] at a rate of 100 g per day, and were allowed to freely drink tap water as drinking water.

As the test drug, amothralol hydrochloride in the form of 0.05% (hereinafter,% represents w / v%) and 1.0% aqueous solution was used. In addition, 0.5% Timolol maleate ophthalmic solution [Tymoptol (registered trademark): Banyu Pharmaceutical Co., Ltd.] was used as a positive control drug, and physiological saline was used as a control substance.

(1) Intraocular pressure measurement 32 rabbits were divided into 4 groups of 8 rabbits per group, and each test drug, control drug and physiological saline solution were instilled into each eye in an amount of 50 μl, and the opposite eye was left untreated. Before and 0.5 instillation
After 1, 2, 3, 4, 6 and 8 hours, a pneuumatonograph (Pneumatonograph: Alcon; hereinafter, referred to as PTG)
Was used to measure the intraocular pressure of both eyes.

FIG. 1 shows the time-dependent changes in the intraocular pressure of each test drug, control drug, and saline solution. The horizontal axis is the time after instillation (hour)
And the vertical axis represents intraocular pressure (mmHg). Each value represents a mean value ± standard error (the number of cases is 8.). a is physiological saline, b is 0.05
% Amosulalol hydrochloride aqueous solution, d means 1.0% amosulalol hydrochloride aqueous solution, and e means 0.5% timolol maleate ophthalmic solution.

As is clear from the results shown in FIG. 1, in the 1.0% amosulalol hydrochloride aqueous solution instillation group, a marked decrease in intraocular pressure continued from 30 minutes after instillation to 6 hours after instillation, and 9.0 m after 3 hours from instillation.
It showed a maximal decrease in intraocular pressure of mHg. In the 0.05% amosulalol hydrochloride aqueous solution instillation group, the maximum intraocular pressure reduction was obtained 2 hours after instillation, and the intraocular pressure reduction was 3.6 mmHg.

In the positive control drug, 0.5% timolol maleate ophthalmic solution, only a slight decrease in intraocular pressure of 2.4 mmHg was obtained 30 minutes after instillation and 1 hour after instillation.

(2) Measurement of pupil diameter For the rabbits used in (1) above, before and after instillation of each test drug and saline solution, 0.5, 1, 2,
After 3, 4 and 6 hours, the pupil diameter of both eyes was measured with a micro caliper.

The pupil diameter of each test drug instilled eye varied within the normal range in any group, and there was no significant change in pupil diameter. Therefore, it is recognized that amosulalol hydrochloride does not affect the pupil diameter.

[Test Example 2] Intraocular pressure-reducing effect of amosulalol hydrochloride on normal intraocular pressure of colored rabbits 40 male colored rabbits (Dutch belted rabbit) weighing about 2 kg
After confirming that there are no abnormalities in the eyes of the animals,
The animals were bred in a breeding room at 4 ° C and a humidity of 55 ± 15%. The feed was 100 g / day of solid feed [Lab RG-RO, Nippon Agricultural Industry Co., Ltd.]
Tap water was provided freely as drinking water.

As the test drug, amosulalol hydrochloride was 0.05%, 0.5%
% And 1.0% aqueous solutions were used. As a positive control drug, 0.5% timolol maleate ophthalmic solution [Thymoptol (registered trademark): Banyu Pharmaceutical Co., Ltd.] was used.
Physiological saline was used as a control substance.

(1) Intraocular pressure measurement Forty rabbits were divided into 5 groups of 8 rabbits per group, and each test drug, control drug and physiological saline solution was instilled into each eye in an amount of 50 μl, and the other eye was untreated. Before and 0.5 instillation
After 1, 2, 3, 4, 6 and 8 hours, the intraocular pressure of both eyes was measured with PTG.

FIG. 2 (treated eye) and FIG. 3 (untreated eye) show the time-dependent changes in intraocular pressure of each test drug, control drug, and physiological saline instilled eye. 2 and 3, the horizontal axis represents time (hour) after instillation, and the vertical axis represents intraocular pressure (mmHg). Each value represents a mean value ± standard error (the number of cases is 8 each). 2 and 3, a is a physiological saline solution, b is a 0.05% aqueous solution of amosulalol hydrochloride, c is a 0.5% aqueous solution of amosulalol hydrochloride,
d means 1.0% amosulalol hydrochloride aqueous solution, and e means 0.5% timolol maleate ophthalmic solution.

As is clear from the results shown in FIG. 2 (treated eye), 1.
In the 0% amosulalol hydrochloride aqueous solution ophthalmic group, a remarkable decrease in intraocular pressure continued from 30 minutes after instillation to 6 hours after instillation, and a maximum intraocular pressure decrease of 0.9 mmHg was observed 3 hours after instillation. In the 0.5% amosulalol hydrochloride aqueous solution instillation group, a significant decrease in intraocular pressure was obtained from 30 minutes after instillation to 4 hours after instillation, and 6.2 mmHg 2 hours after instillation.
Showed a maximum decrease in intraocular pressure. In the 0.05% amosulalol hydrochloride aqueous solution instillation group, the maximum intraocular pressure reduction was obtained 2 hours after instillation, and the intraocular pressure reduction was 3.6 mmHg.

In the positive control drug, 0.5% timolol maleate ophthalmic solution, only a slight decrease in intraocular pressure of 2.4 mmHg was obtained 30 minutes after instillation and 1 hour after instillation.

Further, as is clear from the results shown in FIG. 3 (untreated eyes), there was no significant change in the intraocular pressure of the opposite eye in each test drug instillation group. Therefore, it is recognized that amosulalol hydrochloride does not affect the opposite eye.

(2) Measurement of pupil diameter For the rabbit used in (1) above, before and after instillation of each test drug and physiological saline 0.5, 1, 2,
After 3, 4 and 6 hours, the pupil diameter of both eyes was measured with a micro caliper.

FIG. 4 is a graph showing the pupil diameter of each group of eye drops obtained by instilling a 0.5% aqueous solution of amosulalol hydrochloride or physiological saline against the normal intraocular pressure of a colored rabbit. The horizontal axis represents the time (hour) after instillation, and the vertical axis represents the pupil diameter (mm). Each value represents a mean value ± standard error (the number of cases is 8.). a means a physiological saline solution, and c means a 0.5% aqueous solution of amosulalol hydrochloride.

As is clear from the results shown in FIG. 4, the pupil diameter of each of the test drug instillation groups varied within the normal range in any of the groups, and there was no significant change in the pupil diameter. Therefore, it is recognized that amosulalol hydrochloride does not affect the pupil diameter.

From the above results, amosulalol hydrochloride showed a significant intraocular pressure lowering effect on the normal intraocular pressure of colored rabbits, and the ocular hypotensive effect was lower than that of 0.5% timolol maleate ophthalmic solution even at a low concentration of 0.05%. It turned out to be strong. Also,
Amosulalol hydrochloride has no effect on pupil diameter, 0.5
When the concentration was less than 10%, only slight conjunctival congestion was observed, indicating that the drug was clinically safe.

[Test Example 3] Intraocular pressure-lowering effect of 0.5% aqueous solution of amosulalol hydrochloride on normal intraocular pressure of colored rabbits for 5 consecutive days. After confirming that there are no abnormalities in the eyes of eight male colored rabbits weighing about 2 kg, It is bred in a breeding room with a temperature of 24 ± 4 ° C and a humidity of 55 ± 15%. The feed is 100 g of solid feed [Lab RG-RO, Nippon Agricultural Industry Co., Ltd.] per day, and tap water is freely available as drinking water. I let it.

Using eight colored rabbits bred as described above, a 0.5% aqueous solution of amosulalol hydrochloride was instilled in one eye and a physiological saline solution was instilled in the opposite eye in an amount of 50 μl each. Measurement of intraocular pressure
Using PTG, on the first and fifth days, before the first instillation and every hour after instillation until 8 hours later, and on the second, third and fourth days, before and after the first instillation Measured after 2 or 3 hours. Furthermore, the measurement was performed 24 hours after the first instillation on the fifth day.

FIG. 5 is a graph showing temporal changes in intraocular pressure of each group by continuous instillation of a 0.5% aqueous solution of amosulalol hydrochloride for 5 days with respect to normal intraocular pressure of colored rabbits. The horizontal axis represents the time (in hours) after instillation, and the vertical axis represents the intraocular pressure (mmHg) (the number of cases is 8.). a
Represents a physiological saline solution, and c represents a 0.5% aqueous solution of amosulalol hydrochloride.

As is clear from the results shown in FIG. 5, on the first day of instillation, a maximum intraocular pressure drop of 4.8 mmHg was observed 2 hours after the first instillation. Four hours later, a second instillation was performed, but no further decrease in intraocular pressure was observed. A significant decrease in intraocular pressure was observed until 2 hours after the second instillation, and returned to the initial intraocular pressure after 24 hours. Two hours after instillation on the second day, a significant decrease in intraocular pressure was observed as in the first day, but no significant decrease was observed on the third day. However, on the fourth day, a significant decrease in intraocular pressure was observed, and on the fifth day, the intraocular pressure was substantially the same as that on the first day at any measurement time.

From the above results, even if a 0.5% aqueous solution of amosulalol hydrochloride was instilled into a colored rabbit three times a day for 5 consecutive days, almost the same degree of intraocular pressure reduction was obtained on any day, and tachyphylaxis of amosulalol hydrochloride was observed. ) Is not recognized.

[Test Example 4] 0.2% of white rabbit drinking water load induced high intraocular pressure.
Intraocular pressure lowering action of 5% aqueous amosulalol hydrochloride solution Five male white rabbits weighing about 2 kg were used, and 0.5 μl of aqueous amosularol hydrochloride solution was instilled into one eye and 50 μl of physiological saline solution was instilled into the other eye. After 30 minutes 37ml water 60ml / kg
Was subjected to a drinking load with an oral sonde. Using PTG, before instillation, 30 minutes after instillation (immediately before drinking water load) and drinking water load 0.5,
After 1, 2, and 4 hours, the intraocular pressure of both eyes was measured.

FIG. 6 is a graph showing the intraocular pressure-lowering effect of a 0.5% aqueous solution of amosulalol hydrochloride with respect to white rabbit drinking water load high intraocular pressure. The horizontal axis represents the time (hour) after the drinking load, and the vertical axis represents the intraocular pressure (mmHg) (the number of cases is 8.). a is a physiological saline solution, c
Represents a 0.5% aqueous solution of amosulalol hydrochloride, respectively.

As is clear from the results shown in FIG. 6, in the case of using the saline solution, the intraocular pressure increased by 8.7 mmHg 30 minutes after the drinking water load.
After hours, it returned to its initial value. In contrast, the 0.5% aqueous solution of amosulalol hydrochloride increased the intraocular pressure only by 3.4 mmHg 30 minutes after drinking water load, indicating a significant inhibitory effect on intraocular pressure increase as compared with the physiological saline instilled eye.

[Test Example 5] Intraocular pressure-lowering effect of 0.5% aqueous amosulalol hydrochloride solution on increase in intraocular pressure after laser irradiation of colored rabbits Using five male colored rabbits weighing about 2 kg, using a 0.5% aqueous solution of amosulalol hydrochloride in one eye, A physiological saline solution was instilled in the eye in an amount of 50 μl each. After 30 minutes, irradiate the laser at 6 spots at equal intervals on the iris of both eyes (spot size: 200μm, p
(ower 0.5W, 0.1 second). Before instillation, 30 drops using PTG
Minutes (just before laser irradiation) and laser irradiation 15, 30,
After 45 minutes, the intraocular pressure of both eyes was measured.

FIG. 7 shows the increase in intraocular pressure after laser irradiation of colored rabbits.
It is a graph which shows the intraocular pressure lowering effect of 0.5% amosulalol hydrochloride aqueous solution. The horizontal axis represents time (minutes) after instillation, and the vertical axis represents intraocular pressure (mmHg) (the number of cases is 8.). a is a saline solution,
c represents a 0.5% aqueous solution of amosulalol hydrochloride, respectively.

As is evident from the results shown in FIG. 7, in the eye drops of physiological saline, an increase in intraocular pressure of 7.9 mmHg was observed 15 minutes after laser irradiation, and returned to the initial value after 45 minutes. On the other hand, 0.
In a 5% aqueous solution of amosularol hydrochloride, the intraocular pressure decreased by 4.5 mmHg 30 minutes after instillation (immediately before laser irradiation), and after 15 minutes from laser irradiation, the intraocular pressure was almost the same as that before instillation. The effect of suppressing pressure rise was observed.

Based on the above results, amosulalol hydrochloride not only shows a significant intraocular pressure lowering effect on normal intraocular pressure in rabbits, but also a remarkable increase in intraocular pressure in rabbits induced by drinking water load or laser irradiation. It has been found that the compound has a strong inhibitory effect on intraocular pressure rise.

[Test Example 6] Formulation study of amosulalol hydrochloride ophthalmic solution Freeze-thaw test (investigation of stabilizer for amosulalol hydrochloride ophthalmic solution) Amosulalol hydrochloride was stable to heat and light in an aqueous solution. However, when the freeze-thaw test was performed using a 0.5% aqueous solution of amosulalol hydrochloride (pH 5.5), the crystals did not dissolve even after being frozen and left at room temperature. For this reason, a stabilizer when frozen was studied.

A 5% glass ampoule was filled with a 0.5% aqueous solution of amosulalol hydrochloride (pH 5.5) to which various stabilizers (Nos. 1 to 5) described in Table 1 below were added, frozen at −30 ° C., and allowed to stand at room temperature. The presence or absence of crystals was examined.

Table 2 shows the results. As is clear from the results shown in Table 2, polyvinylpyrrolidone K-30 (stabilizer No. 2) and α-cyclodextrin (stabilizer No. 4)
Was effective. Therefore, it was found that polyvinylpyrrolidone or α-cyclodextrin is preferably used as the stabilizer for amosulalol hydrochloride, and it is more preferable to use polyvinylpyrrolidone.

[Test Example 7] Toxicity test of amosulalol hydrochloride (1) Acute toxicity test of amosulalol hydrochloride using mice The acute toxicity of amosulalol hydrochloride in mice was examined by oral administration or intravenous administration.

Using 7-week-old ICR mice, amosulalol hydrochloride was orally administered by an oral probe or via the tail vein using a syringe. As a result, the 50% lethal dose (LD ₆₀ ) was 6500 mg / kg (male) and 5700 mg / kg (female) by oral administration, and 104 mg / kg (male) and 134 mg / kg (female) by intravenous administration. .

(2) Ocular Local Toxicity Test by Injection of 1.0% and 0.5% Amosulalol Hydrochloride Ophthalmic Solution into Rabbits for 28 Consecutive Days Using 15 Japanese White Male Rabbits in Groups of 5 in Each Group [Example 5] The ophthalmic solution of Example 5 having an amosulalol hydrochloride amount of 1.0 g (hereinafter referred to as 1.0% amosulalol hydrochloride ophthalmic solution) and the ophthalmic solution of Example 5 (hereinafter referred to as 0.5% amosulalol hydrochloride ophthalmic solution) were used.
As a control substance, a physiological saline solution was instilled in the right eye only once at a time (0.05 ml) four times a day at 2.5 hour intervals for 28 consecutive days. At that time, the left eye was left untreated.

The observation was performed for the following items (1) to (6).

(1) General condition The general condition was observed once a week.

(2) Measurement of body weight The body weight was observed once a week.

(3) Macroscopic observation of the anterior eye part Eye damage criteria described below (Contemporary clinic, Volume 4,
No. 7, Showa 45, pp. 227-289) based on 1.0%
Before instillation of 0.5% amosulalol hydrochloride ophthalmic solution, on the first day of instillation (day 1), after 2,4,7,14,21 and 28 days after the start of instillation, and in the morning after the last administration (day 29) Was evaluated. Regarding the scoring results, if a score of 1 or more is found in any of the items, it is regarded as impaired, and 0 and 0.
5 has no abnormality.

Criteria for determining eye damage Cornea (A) Opaque ・ No cloudiness (normal): 0 ・ Diffuse areas are scattered (details of the iris are clearly visible): 1 ・ Translucent area which is easily distinguished (iris (Details are somewhat unclear): 2-Opaque area, iris details are not visible, barely discernible pupil size: 3-Opaque, iris not visible: 4 (B) Cornea area corresponding to above Size-1/4 or less, not 0: 1-Greater than 1/4 and less than 1/2: 2-Greater than 1/2 and less than 3/4: 3-3/4 or more and over the entire area Reached: 4 Iris evaluation ・ Normal: 0 ・ Over normal folds, congestion, wetness, hyperemia around the cornea (any one or a combination thereof) are observed. Iris still responds to light (slow positive response): 1 ・ No response to light, bleeding, significant destruction (any or all of them): 2 Conjunctiva (A) Eyelid conjunctival redness ・ Redness observed Not possible: 0 ・ Conjunctiva is very light reddish, and slight dilation of blood vessels around the eye margin is observed: 0.5 ・ Clear hyperemia beyond normal, redness of conjunctiva becomes clear and irritability Remarkable: 1 ・ Redness of the eyelid conjunctiva became very remarkable, and the running of the terminal blood vessels was slightly unclear: 2 ・ More intense of the above 2 showing diffuse infiltrating beef-like redness: 3 ( B) Eyelid conjunctival edema-No swelling: 0-Slight tendency to edema: 0.5-Some swelling more than normal: 1-Apparent swelling and valgus in part of eyelid With: 2 ・ Swell and close about half of eyelid 3: Swelled and completely closed from about half of the eyelid: 4 (C) Redness of bulbar conjunctiva ・ No hyperemia: 0 ・ Slight expansion of blood vessels around cornea: 0.5 ・ More pronounced When severe vasodilation occurs: 1-When the dilation of blood vessels running toward the eyelid margin is remarkable, or when it is remarkably reddish: 2 (D) State of nictitating membrane-No hyperemia is observed: 0- Degree of tendency of vasodilation and edema: 0.5 ・ Dilation of blood vessels becomes more pronounced and eyelid margin is lean: 1 ・ Vascular vasodilation is marked, and entire nictitating membrane is markedly reddish: 2 ( E) Secretions • No secretions: 0 • Some amount of secretions different from normal (except for small amounts found in the internal canthus of normal animals): 1 • There is secretions and eyelids And wet the hair in contact with the eyelids: 2 Yes, wetting the hair of the eyelid and a considerable area around the eye: 3 The results of the macroscopic observation of the anterior segment of the eye in the above (3) are shown in Table 5 for 1.0% amosulalol hydrochloride ophthalmic solution, and 0.5% amosulalol hydrochloride. Table 6 shows the ophthalmic solutions. Table 5
And the scoring value of the cornea in Table 6 is obtained by multiplying “(A) opacity” and “(B) size of the corneal region corresponding to the above” in “cornea” of the above “eye disorder determination criteria”. Mean value. Each value is an average of five cases.

(4) Observation of fluorescein-stained spots on the cornea Before and after the instillation of 1.0% and 0.5% amosulalol hydrochloride ophthalmic solution, on the first day of instillation, and on the 2,4,7,14,21 and 28 days after the start of instillation After termination and on the morning following the final administration (day 29), 10 μl of a 0.1% fluorescein aqueous solution was instilled, and exfoliation of corneal epithelial cells was observed using a photo slit lamp.

(5) Evaluation of corneal epithelium and endothelial cells by scanning electron microscope After the instillation of 1.0% and 0.5% amosulalol hydrochloride ophthalmic solution, the morphology of corneal epithelium and endothelial cells in each of the three cases in both groups were observed.

(6) Evaluation of sagittal cross section of eyeball by optical microscope After completion of instillation of 1.0% and 0.5% amosulalol hydrochloride ophthalmic solution, light microscope specimens of sagittal cross section of the eyeball were prepared for each of two cases in both groups, and the eyelid, conjunctiva, The cornea, anterior chamber, iris, lens, vitreous, retina / choroid, sclera and optic nerve were examined microscopically.

As a result, in (1) general condition and (2) body weight measurement, no abnormalities were observed in any of 1.0% and 0.5% amosulalol hydrochloride ophthalmic solution. Also,
(3) In the macroscopic observation of the anterior segment, as is clear from the results shown in Tables 5 and 6, no abnormalities were observed in any of the 1.0% and 0.5% amosulalol hydrochloride ophthalmic solutions. Furthermore, 1.0% and 0.5% were observed in (4) observation of fluorescein staining spots on the cornea, (5) evaluation of corneal epithelium and endothelial cells by a scanning electron microscope, and (6) evaluation of a sagittal section of an eyeball by an optical microscope. No abnormality was observed in any of the% amosulalol hydrochloride ophthalmic solutions.

From the results of the above various tests, amosulalol hydrochloride
When used as eye drops for treating glaucoma, it is recognized as a very safe drug without side effects such as eye irritation.

INDUSTRIAL APPLICABILITY The pharmaceutical composition for treating glaucoma of the present invention has an excellent intraocular pressure lowering effect at a low concentration, and has low toxicity and is stable.
It is advantageously used as a pharmaceutical composition for treating various glaucoma.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/32 A61K 47/32 J 47/40 47/40 J (72) Inventor Katsuhiro Inada 4 Kamihigashi, Hirano-ku, Osaka-shi, Osaka Citation No. 20-2 (56) References JP-A-54-95544 (JP, A) JP-A-55-73609 (JP, A) JP-A-2-240053 (JP, A) JP, B2)

Claims (8)

(57) [Claims] (1) Expression Pharmaceutical composition for treating glaucoma, comprising 5- {1-hydroxy-2- [2- (2-methoxyphenoxy) ethylamino] ethyl} -2-methylbenzenesulfonamide or an acid salt thereof represented by the formula: . 2. The method according to claim 2, wherein the 5- (1-hydroxy-2- [2- (2-
The pharmaceutical composition for treating glaucoma according to claim 1, which comprises methoxyphenoxy) ethylamino] ethyl} -2-methylbenzenesulfonamide or an acid salt thereof, and polyvinylpyrrolidone or α-cyclodextrin. 3. The pharmaceutical composition for treating glaucoma according to claim 1, wherein the dosage form of the composition is an eye drop. 4. The pharmaceutical composition for treating glaucoma according to claim 1, wherein the dosage form of the composition is an ophthalmic ointment. (5) 5- {1-hydroxy-2- [2- (2-methoxyphenoxy) ethylamino] ethyl} -2-methylbenzenesulfonamide or an acid salt thereof represented by the formula: Stuff. 6. A method according to claim 6, wherein 5- {1-hydroxy-2- [2- (2-
The pharmaceutical composition for lowering intraocular pressure according to claim 5, which comprises methoxyphenoxy) ethylamino] ethyl} -2-methylbenzenesulfonamide or an acid salt thereof, and polyvinylpyrrolidone or α-cyclodextrin. 7. The pharmaceutical composition for reducing intraocular pressure according to claim 1, wherein the dosage form of the composition is an eye drop. 8. The pharmaceutical composition for reducing intraocular pressure according to claim 1, wherein the dosage form of the composition is an ophthalmic ointment.