JP2010090052A - Ophthalmic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ophthalmic agent while blending alginic acid or its salt as a sustained releasing component, without developing a problem of decreasing viscosity over time. <P>SOLUTION: The ophthalmic agent contains (A) timolol maleate, (B) trometamol, (C) alginic acid or its salt and (D) an inorganic metal salt. The (M/G) ratio of the alginic acid is made as ≤2.0. The inorganic metal salt is made as potassium chloride and/or sodium chloride. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an ophthalmic agent, and more particularly to an ophthalmic agent that contains timolol maleate as an active ingredient and that suppresses a decrease in viscosity over time.

  In the treatment of glaucoma, various eye drops are often used generally in anticipation of an intraocular pressure lowering effect. Specific examples of eye drops used for glaucoma include β-blockers such as carteolol hydrochloride, timolol maleate, betaxolol hydrochloride, α-blockers such as bunazosin hydrochloride, αβ-blockers such as levobunolol hydrochloride and nipradilol Carbonic acid dehydrogenase inhibitors such as purinzolamide and dorzolamide hydrochloride, prostaglandin drugs such as latanoprost and isopropyl unoprostone, sympathomimetic drugs such as dipivefrin hydrochloride, and parasympathomimetic drugs such as pilocarpine hydrochloride. .

  By the way, many eye drops for treating glaucoma have insufficient duration of intraocular pressure reduction, and the number of administrations per day is two times. It has been desired to do so, and attempts have been made to do so.

  As an example of a technique for making an ophthalmic agent into a continuous preparation, a sustained-release preparation by using a polymer compound and increasing the viscosity of the drug is known. For example, Patent Document 1 discloses a topical medicinal composition containing ramsan gum, and Patent Document 2 discloses a local ophthalmic composition comprising a gelled polysaccharide and a finely pulverized drug carrier. Yes.

  Patent Document 3 contains an ophthalmic composition containing a carbonic anhydrase inhibitor and xanthan gum. Patent Document 4 contains a base that causes a liquid-gel phase transition on the ocular surface, such as methylcellulose. Furthermore, a glaucoma or ocular hypertension therapeutic agent containing a β-blocker and an intraocular pressure-lowering drug other than the β-blocker is disclosed.

  In addition, U.S. Patent No. 6,057,017 includes an ophthalmology comprising xanthan gum having a total ionic strength of about 120 mM or less and having an initial bound acetate content of at least about 4% and an initial bound pyruvate content of at least about 2.5%. A composition for use is disclosed.

Further, Patent Document 6 discloses a β-blocker solution obtained by dissolving a β-blocker in water in the presence of alginic acid, and adding an alkaline base thereto to adjust the pH of the solution to 6-8. The ophthalmic pharmaceutical composition to be contained in Patent Document 7 is selected from alginic acid derivatives having an M / G ratio of 1.0 or less, phosphoric acid and its salt, and tris (hydroxymethyl) aminomethane and its salt A liquid composition containing one or more compounds is disclosed in Patent Document 8 as a liquid composition containing an alginic acid derivative and boric acid and / or a salt thereof.
JP-A-64-034926 Japanese Patent Application Laid-Open No. 07-010776 Special table 2001-508035 Special table 2001-081048 Special table 2002-510654 Special table 2002-511430 JP 2002-332248 A JP 2002-332249 A

  Various sustained-release preparations have been provided by the techniques disclosed in the above-mentioned documents. Among these, alginic acid was investigated by the present inventors regarding ophthalmic agents using alginic acid or a salt thereof. It has been found that the ophthalmic preparation formulated with a decrease in viscosity over time immediately after preparation. And it became clear that the fluctuation | variation of these physical-property values is a cause which impairs remarkably the functions peculiar to formulations, such as sustained release property and functionality.

  As a result of diligent research to solve the above-mentioned problems, the present inventors have found that, in an ophthalmic preparation containing timolol maleate as an active ingredient, the combined use of trometamol and a specific alginic acid or a salt thereof and a metal inorganic salt Has been found to be an ophthalmic agent that does not easily decrease over time, and has led to the present invention.

That is, the present invention
(A) Timolol maleate (B) Trometamol (C) Alginic acid or a salt thereof (D) An ophthalmic preparation that contains a metal inorganic salt and is capable of suppressing a decrease in viscosity over time.

  Since the ophthalmic preparation of the present invention is one in which a decrease in viscosity over time is suppressed, functions such as sustained release and functionality do not decrease, and is excellent in the treatment of glaucoma.

  The active ingredient of the ophthalmic preparation of the present invention is timolol maleate, which is blended as component (A). The amount of component (A) is usually 0.01 to 5 w / v% in the ophthalmic preparation, preferably 0.05 to 3 w / v%, more preferably 0.1 to 1 w / v%. It is.

  Moreover, the ophthalmic agent of the present invention contains trometamol as the component (B). The amount of component (B) is not particularly limited, but is usually 0.01 to 10 w / v%, preferably 0.05 to 5 w / v% in ophthalmic preparations, more preferably 0.1 to 0.1%. 2 w / v%. If the blending amount of component (B) is less than 0.01 w / v%, the enhancing action for increasing the viscosity of alginic acid is insufficient, and if it exceeds 10 w / v%, it is not preferable from the viewpoint of eye irritation.

  Furthermore, the ophthalmic agent of the present invention contains alginic acid or a salt thereof as component (C). This alginic acid is a kind of polysaccharide contained in brown algae and the like, and is composed of two blocks of s-D-mannuronic acid (M) and α-L-guluronic acid (G) which is its C-5 epimer (both are both Monosaccharide having a carboxyl group) is a linear polymer with (1-4) -bonded. Examples of the alginic acid or a salt thereof include alginic acid, alginic acid sodium salt, potassium salt, triethanol salt, and alginic acid salt such as ammonium salt. Among these, alginic acid and sodium alginate are particularly preferable.

  The M / G ratio in the alginic acid or a salt thereof is usually 0.5 or more and 2.0 or less, preferably 0.7 or more and 1.8 or less, more preferably 1.0 or more and 1.6 or less. . Here, the M / G ratio means a block ratio of sD-mannuronic acid (M) and α-L-guluronic acid (G) which is its C-5 epimer.

  The M / G ratio of alginic acid or a salt thereof can be measured according to a known method, for example, the method described in (“Carbohydrate Research”, 32 (1974), 217-225). That is, alginic acid includes an MM fraction, a GG fraction, and an MG fraction, which differ in resistance to hydrolysis and solubility in acid. Therefore, after degrading with weak hydrochloric acid under conditions that allow cleavage into the MM, GG, and MG fractions, each fraction is fractionated according to a conventional method, and the sugar content of each fraction is further determined. The M / G ratio can be calculated by measuring with the phenol-sulfuric acid method.

  The amount of component (C) is not particularly limited, but is usually 0.01 to 10 w / v%, preferably 0.05 to 5 w / v% in ophthalmic preparations, more preferably 0.1 to 0.1%. 2 w / v%. When the blending amount of component (C) is less than 0.01 w / v%, the enhancing action for increasing the viscosity of alginic acid is insufficient, and when it exceeds 10 w / v%, it is not preferable from the viewpoint of eye irritation.

  Furthermore, examples of the inorganic metal salt blended as the component (D) of the present invention include alkali metal salts such as potassium chloride, sodium chloride, sodium carbonate, sodium bicarbonate, sodium nitrate, sodium sulfate. Of these, sodium chloride and potassium chloride are particularly preferred.

  The amount of component (D) is not particularly limited, but is generally 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 2 w in ophthalmic preparations. / V%. If the blending amount of component (D) is less than 0.01 w / v%, the ophthalmic preparation may have an insufficient inhibitory effect on the decrease in viscosity over time, and if it exceeds 10 w / v%, It is not preferable from the viewpoint of irritation.

  The ophthalmic preparation according to the present invention is prepared by, for example, blending the above components (A) to (D) in a suitable liquid carrier such as water and mixing them by a known general procedure.

  In preparing the ophthalmic preparation of the present invention, in addition to the above-described components, a buffer, preservative, thickener, pH adjuster, cooling agent, surfactant, isotonic agent, etc. Additives can be added.

  Among the additives, examples of the buffer include phosphoric acid or a salt thereof, boric acid or a salt thereof, acetic acid or a salt thereof, tartaric acid or a salt thereof, citric acid or a salt thereof, and the like.

  Examples of preservatives include chlorhexidine gluconate, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid Examples of thickeners include hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyvinyl polymer, hypromellose, polyvinyl alcohol, methyl cellulose, gum arabic, povidone, and xanthan gum. Can do.

  Furthermore, examples of the pH regulator include hydrochloric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc. Examples of the cooling agent include menthol, camphor, borneol, Geraniol, eucalyptus oil, mint oil and the like can be mentioned.

  In addition, examples of the surfactant include polyoxyethylene sorbitan laurate (polysorbate 20), polyoxyethylene sorbitan palmitate (polysorbate 40), polyoxyethylene sorbitan stearate (polysorbate 60), polyoxyethylene sorbitan tristearate. (Polysorbate 65), polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan oleate (polysorbate 80); polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxy Polyoxyethylene hydrogenated castor oil such as ethylene hydrogenated castor oil 60; polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68) Polyoxyethylene (42) Polyoxypropylene (67) Glycol (Pluronic P123), Polyoxyethylene (54) Polyoxypropylene (39) Glycol (Pluronic P85), Polyoxyethylene (196) Polyoxypropylene (67) Glycol ( Pluronic F127), polyoxyethylene (20) polyoxypropylene (20) glycol (pluronic L-44) and other polyoxyethylene polyoxypropylene glycols; polyethylene glycol monolaurate, ethylene glycol monostearate, polyethylene glycol monostearate, Polyethylene glycol monooleate, ethylene glycol monostearate, ethylene glycol distearate, polyethylene glycol distearate Calls, such as polyethylene glycol fatty acid esters such diisostearate polyethylene glycol. Among these, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyethylene glycol fatty acid ester are particularly preferable, and among them, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyoxyl 40 stearate are more preferable.

  Examples of isotonic agents include glycerin, propylene glycol, macrogol 400, glucose, sucrose, mannitol, sorbitol and the like.

  The pH of the ophthalmic preparation according to the present invention is typically 5-9, preferably 5.5-8.5, more preferably 6-8. If the pH deviates from the range of 5 to 9, irritation may be felt during instillation, which is not preferable.

  Moreover, the osmotic pressure ratio of the ophthalmic preparation according to the present invention is usually 0.5 to 1.5, preferably 0.7 to 1.3, more preferably 0.9 to 1.1. If the osmotic pressure ratio deviates from the range of 0.5 to 1.5, it is not preferable because irritation may be felt during instillation.

  The contents of the present invention will be described in more detail with reference to the following examples, test examples and comparative examples, but the present invention is not limited to the contents of these examples and the like.

Example 1
After adding 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.342 g of timolol maleate (0.25 g as timolol) to about 70 g of purified water and dispersing, 0.71 g was added and dissolved by stirring until the liquid became clear. To this, 0.74 g of sodium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic preparation. The ophthalmic preparation had a pH of 6.98.

Example 2
To about 70 g of purified water, 1.00 g of alginic acid (duck acid A; M / G ratio: about 0.9) and 0.342 g of timolol maleate (0.25 g as timolol) were added and dispersed. 0.71 g was added and dissolved by stirring until the liquid became clear. To this, 0.74 g of sodium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic preparation. The ophthalmic preparation had a pH of 7.52.

Comparative Example 1
After adding 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.342 g of timolol maleate (0.25 g as timolol) to about 70 g of purified water and dispersing, .70 g was added and dissolved by stirring until the liquid became clear. To this, 2.40 g of glycerin and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make a total volume of 100 mL to obtain an ophthalmic preparation. The pH of this ophthalmic preparation was 6.89.

Comparative Example 2
To about 70 g of purified water, 1.00 g of alginic acid (duck acid A; M / G ratio: about 0.9) and 0.342 g of timolol maleate (0.25 g as timolol) were added and dispersed. .70 g was added and dissolved by stirring until the liquid became clear. To this, 2.40 g of glycerin and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make a total volume of 100 mL to obtain an ophthalmic preparation. The ophthalmic preparation had a pH of 7.59.

Comparative Example 3
To about 70 g of purified water, 1.00 g of alginic acid (Duck Acid A; M / G ratio: about 0.9) and nipradilol (manufactured by Katsura Chemical Co., Ltd., the same applies below) 0.25 g were added and dispersed. 0.60 g of trometamol was added and dissolved by stirring until the liquid became clear. To this, 2.42 g of glycerin and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then the pH was adjusted to about 7 using dilute hydrochloric acid. Purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic drug. The pH of this ophthalmic drug was 7.25.

Comparative Example 4
After adding 1.00 g of alginic acid (Duck Acid A; M / G ratio: about 0.9) and 0.25 g of nipradilol to about 70 g of purified water, 0.60 g of trometamol is added, and the liquid becomes clear. Stir until dissolved. To this, 0.06 g of glycerin, 0.70 g of sodium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then the pH was adjusted to about 7 using dilute hydrochloric acid. Purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic drug. The pH of this ophthalmic drug was 7.12.

Comparative Example 5
To about 70 g of purified water, 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.25 g of nipradilol were added and dispersed, and then 0.68 g of trometamol was added to make the liquid clear. Stir until dissolved. To this, 2.42 g of glycerin and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then the pH was adjusted to about 7 using dilute hydrochloric acid. Purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic drug. The pH of this ophthalmic drug was 7.14.

Comparative Example 6
To about 70 g of purified water, 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.25 g of nipradilol were added and dispersed, and then 0.68 g of trometamol was added to make the liquid clear. Stir until dissolved. To this, 0.06 g of glycerin, 0.70 g of sodium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then the pH was adjusted to about 7 using dilute hydrochloric acid. Purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic drug. The pH of this ophthalmic drug was 7.01.

Comparative Example 7
After adding 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.25 g of nipradilol to about 70 g of purified water, 0.21 g of monoethanolamine was added and Stir until dissolved to dissolve. To this, 2.67 g of glycerin and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make a total volume of 100 mL to obtain an ophthalmic solution composition. The ophthalmic solution composition had a pH of 6.81.

Comparative Example 8
After adding 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.25 g of nipradilol to about 70 g of purified water, 0.21 g of monoethanolamine was added and Stir until dissolved to dissolve. To this, 0.30 g of glycerin, 0.70 g of potassium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make up a total volume of 100 mL. Obtained. The ophthalmic solution composition had a pH level of 6.95.

Comparative Example 9
To about 70 g of purified water, 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) was added and dispersed, and then 0.625 g of trometamol was added and stirred until the liquid became clear. Dissolved. To this, 0.70 g of sodium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic solution composition. The ophthalmic solution composition had a pH level of 6.95.

Comparative Example 10
To about 70 g of purified water, 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) was added and dispersed, and then 0.625 g of trometamol was added and stirred until the liquid became clear. Dissolved. To this, 0.70 g of potassium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then the pH was adjusted to about 7 using dilute hydrochloric acid. An ophthalmic solution composition was obtained. The ophthalmic solution composition had a pH level of 6.95.

Comparative Example 11
After adding 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.342 g of timolol maleate (0.25 g as timolol) to about 70 g of purified water and dispersing, Sodium was added and dissolved by stirring until the liquid was clear. To this, 0.70 g of sodium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make up a total volume of 100 mL to obtain an ophthalmic solution composition. The ophthalmic solution composition had a pH of 7.08.

Comparative Example 12
After adding 1.00 g of alginic acid (Kimika Acid SA; M / G ratio: about 1.6) and 0.342 g of timolol maleate (0.25 g as timolol) to about 70 g of purified water and dispersing, .60 g was added and dissolved by stirring until the liquid became clear. To this was added 0.02 g of benzalkonium chloride solution (10%) and dissolved, and then purified water was added thereto to make a total volume of 100 mL to obtain an ophthalmic drug. The pH of this ophthalmic drug was 6.80.

Comparative Example 13
After adding 1.00 g of alginic acid (duck acid A; M / G ratio: about 0.9) to about 70 g of purified water and dispersing, add 0.53 g of trometamol and stir until the liquid becomes clear. Dissolved. To this, 0.70 g of sodium chloride and 0.02 g of benzalkonium chloride solution (10%) were added and dissolved, and then purified water was added thereto to make a total volume of 100 mL to obtain an ophthalmic drug. The pH of this ophthalmic drug was 6.72.

Test Example Each ophthalmic preparation obtained in Examples 1 and 2 and Comparative Examples 1 to 13 was stored for 4 weeks under the condition of 60 ° C., and the viscosity was measured before and after that. At this time, in order to reproduce the gelation by tears at the time of instillation, 0.5 mL of 0.01 mol / L calcium chloride aqueous solution was added to each 0.5 mL of ophthalmic preparation, and measurement was performed. Viscosity measurement is a cone-plate type digital viscometer (manufactured by Brookfield), an E-type viscometer, and the section “Conical one plate rotary viscometer” in the viscosity measurement method described as a general test method of the Japanese Pharmacopoeia. The measurement was performed at a measurement temperature of 25 ° C. and a measurement rotation speed of 20 rpm. The results are shown in Table 1. In the table, the compositions of Examples 1 and 2 and Comparative Examples 1 to 13 are also shown.

  From the above test examples, it was found that the ophthalmic preparations of Examples 1 and 2 are less likely to cause a decrease in viscosity over time as compared with the ophthalmic preparations of Comparative Examples 1 to 13.

  The ophthalmic drug of the present invention is less susceptible to a decrease in viscosity after storage than conventional ones, and maintains sustained release and sustainability.

  Therefore, the ophthalmic preparation of the present invention can be widely used as a continuous eye drop for treating glaucoma.

Claims (3)

The following components (A) to (D)
(A) Timolol maleate (B) Trometamol (C) Alginic acid or a salt thereof (D) An ophthalmic agent characterized by containing an inorganic metal salt.   The ophthalmic preparation according to claim 1, wherein the M / G ratio of alginic acid is 2.0 or less. The ophthalmic preparation according to claim 1 or 2, wherein the inorganic metal salt is potassium chloride and / or sodium chloride.