JP6702754B2 - Preservative containing dorzolamide - Google Patents

Description

The present invention relates to dorzolamide or a salt thereof.

Dorzolamide, which is a carbonic anhydrase inhibitor, is useful for the treatment of glaucoma or ocular hypertension because it exhibits an intraocular pressure-lowering action, and a preparation containing dorzolamide is sold as Torsopt (registered trademark) eye drop. Further, it is described in Patent Document 1 that a composition containing both dorzolamide and timolol is useful for the treatment of ocular hypertension, and a formulation containing dorzolamide and timolol is used as a Cosopt (registered trademark) combination ophthalmic solution. It is sold.

Furthermore, the eye drops require a certain level of antiseptic effect in order to prevent the propagation of fungi and the like due to repeated use, and the above-mentioned Torsopt (registered trademark) eye drops and Torsopt (registered trademark) combination eye drops are required. Benzalkonium chloride is mixed as a preservative. On the other hand, in consideration of the effect of benzalkonium chloride on patients, Cosopt (registered trademark) combination ophthalmic solution containing no benzalkonium chloride is also sold. Since the eye drop does not contain a preservative, a single-use unit dose container or a PFMD (Preservative Free Multi Dose) container is used. In other words, eye drops containing dorzolamide are recognized as having to preserve the antiseptic effect by containing benzalkonium chloride or the structure of the container for repeated use. It is not known to have an antiseptic effect.

A composition containing Dorzolamide and exhibiting an antiseptic effect without containing benzalkonium chloride is described in Patent Document 2, but a certain amount of boric acid is added in order to exert an antiseptic effect. Alternatively, it does not disclose that the salt itself has an antiseptic effect.

Japanese Patent No. 2527513 International publication WO2011/013794 pamphlet

An object of the present invention is to provide a new use of dorzolamide or a salt thereof.

The present inventors have surprisingly found that a pharmaceutical composition containing dorzolamide or a salt thereof can sufficiently exert an antiseptic effect, even though it does not contain other antiseptics, and to complete the present invention. I arrived. Specifically, the present invention provides the following.

(1) A preservative containing dorzolamide or a salt thereof.

(2) The preservative according to (1) for a pharmaceutical composition to be placed in a multi-dose type container.

(3) The preservative according to any one of (1) or (2) for a pharmaceutical composition containing no benzalkonium chloride.

(4) The preservative according to any one of (1) to (3) for a pharmaceutical composition containing no boric acid or a salt thereof.

(5) The preservative according to any one of (1) to (4), wherein the dorzolamide or its salt is dorzolamide hydrochloride.

(6) The preservative according to any one of (1) to (5), which is used in combination with edetic acid or a salt thereof.

(7) The preservative according to (6), wherein the salt of edetic acid is monosodium edetate, disodium edetate, tetrasodium edetate or disodium edetate dihydrate.

(8) A pharmaceutical composition containing the preservative according to any one of (1) to (7), containing no preservative other than the preservative or containing a predetermined amount of the preservative.
The predetermined amount is such that the concentration of the bacterial solution of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample consisting of a preservative other than the preservative and water. After inoculating the cells with the bacteria and mixing them evenly and storing the test sample at 20 to 25° C. in the dark, 28 days after the test sample, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The ratio of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) at that time is 4.0 or less.
When boric acid or a salt thereof is contained in the pharmaceutical composition, the content thereof is less than 0.001% (w/v), and the composition is contained in a reusable container.

(9) The pharmaceutical composition according to (8), which contains 0.0001 to 0.1% (w/v) of edetic acid or a salt thereof.

(10) A pharmaceutical composition containing the preservative according to any one of (1) to (7), wherein the preservative and the preservative other than edetic acid and a salt thereof are not included.
Containing 0.0001 to 0.1% (w/v) of edetic acid or a salt thereof,
A pharmaceutical composition in a reusable container.

(11) It contains the preservative according to any one of (1) to (7), does not contain benzalkonium chloride, does not contain dorzolamide and its salts, and preservatives other than the above preservatives. Or a pharmaceutical composition containing a predetermined amount,
The predetermined amount is such that the concentration of the bacterial solution of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample consisting of a preservative other than the preservative and water. After inoculating the cells with the bacteria and mixing them evenly and storing the test sample at 20 to 25° C. in the dark, 28 days after the test sample, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The ratio of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) at that time is 4.0 or less.
Containing 0.0001 to 0.1% (w/v) of edetic acid or a salt thereof,
When boric acid or a salt thereof is contained in the pharmaceutical composition, the content thereof is less than 0.001% (w/v), and the composition is contained in a reusable container.

(12) The pharmaceutical composition according to any one of (8) to (11), wherein the content of dorzolamide or a salt thereof is 0.1-5% (w/v).

(13) The pharmaceutical composition according to any one of (8) to (12), which contains Dorzolamide or a salt thereof as an active ingredient of a medicine.

(14) A product comprising the pharmaceutical composition according to any one of (8) to (13) and a container that can be repeatedly used.

(15) A method of improving preservative efficacy by incorporating dorzolamide or a salt thereof in a pharmaceutical composition contained in a container that can be used repeatedly.

It is possible to arbitrarily select and combine two or more of the configurations (1) to (15).

According to the present invention, a preservative containing dorzolamide or a salt thereof can be provided. Further, it is possible to provide a new pharmaceutical composition containing dorzolamide or a salt thereof, which is capable of sufficiently exhibiting the antiseptic effect even when the container is repeatedly opened and closed for use.

The present invention will be described in detail below.
Dorzolamide contained in the preservative of the present invention has a chemical name (4S, 6S)-4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7 , A compound represented by 7-dioxide.

The dorzolamide contained in the preservative of the present invention may be a salt and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of salts include salts with inorganic acids, salts with organic acids, quaternary ammonium salts, salts with halogen ions, salts with alkali metals, salts with alkaline earth metals, metal salts, salts with organic amines, etc. Can be mentioned.
Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
As the salt with an organic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucohepto acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
Examples of the quaternary ammonium salt include salts with methyl bromide, methyl iodide and the like.
Examples of salts with halogen ions include salts with chloride ions, bromide ions, iodide ions and the like.
Examples of the salt with an alkali metal include salts with lithium, sodium, potassium and the like.
Examples of the salt with an alkaline earth metal include salts with calcium, magnesium and the like.
Examples of the metal salt include salts with iron, zinc and the like.
Examples of salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxy). Examples thereof include salts with methyl)-1,3-propanediol, procaine, N,N-bis(phenylmethyl)-1,2-ethanediamine and the like.
As the salt of dorzolamide, monohydrochloride (dorzolamide hydrochloride) is particularly preferable.

Dorzolamide and salts thereof contained in the preservative of the present invention may be in the form of hydrate or solvate.

The preservative of the present invention contains dorzolamide or a salt thereof, but dorzolamide or a salt itself may be the preservative of the present invention.

The preservatives of the present invention can be used for pharmaceutical compositions.

Since the antiseptic of the present invention has an antiseptic effect by itself, it is suitable for use in a pharmaceutical composition containing no antiseptic other than the antiseptic of the present invention. For example, the use of the preservative of the present invention is as follows: a pharmaceutical composition containing no benzalkonium chloride, a pharmaceutical composition containing no boric acid or a salt thereof, a pharmaceutical composition containing no quaternary ammonium salt other than benzalkonium chloride. It can be used for compositions and the like.

In the pharmaceutical composition in which the preservative of the present invention is used, the content of dorzolamide or a salt thereof contained is not particularly limited as long as it is an amount sufficient to achieve a desired preservative effect, but 0.1 to 5 % (W/v) is preferable, 0.2 to 3% (w/v) is more preferable, 0.3 to 2% (w/v) is further preferable, and 0.3 to 1.2% (w/v). v) is even more preferable, 0.3-1.0% (w/v), 0.3-0.7% (w/v), 0.3-0.5% (w/v) is more preferable. Preferably 0.5% (w/v), 1% (w/v) or 2% (w/v). In addition, when the salt of dorzolamide is contained in the pharmaceutical composition in which the preservative of the present invention is used, these values are the contents converted into free dorzolamide. In addition, "% (w/v)" means the mass (g) of the target component (here, dorzolamide) contained in 100 mL of the pharmaceutical composition of the present invention. The same applies hereinafter unless otherwise specified.

The preservative of the present invention may be used in combination with timolol or a salt thereof in order to exert the preservative effect. Timolol has the chemical name (2S)-1-[(1,1-Dimethylethyl)amino]-3-(4-morpholin-4-yl-1,2,5-thiadiazol-3-yloxy)propan-2- It is a compound represented by ol. "Use in combination" means containing the preservative of the present invention and timolol or a salt thereof in one pharmaceutical composition.

The timolol used in combination in the preservative of the present invention may be a salt, and there is no particular limitation as long as it is a pharmaceutically acceptable salt, and specifically, the examples of the salt of dorzolamide were mentioned. Salts are mentioned, the monomaleic acid salt (timolol maleic acid salt) being particularly preferred.

Timolol and salts thereof used in combination in the preservative of the present invention may take the form of a hydrate or a solvate.

In the pharmaceutical composition in which the preservative of the present invention is used, the content of timolol or a salt thereof used in combination is not particularly limited as long as it is an amount sufficient to achieve the desired preservative effect, but 0.01 2% (w/v) is preferable, 0.05-1% (w/v) is more preferable, 0.1-0.8% (w/v) is further preferable, and 0.2-0.7. % (W/v) is even more preferred, and 0.5% (w/v) is especially preferred. In addition, when a salt of timolol is contained in the pharmaceutical composition of the present invention, these values are contents converted into free timolol.

In the preservative of the present invention, when used in combination with timolol or a salt thereof, the content of dorzolamide or a salt thereof in the pharmaceutical composition is from the viewpoint of the antiseptic effect, the content of timolol or a salt thereof in the pharmaceutical composition. On the other hand, it is preferably 0.1 to 10 times, more preferably 0.5 to 8 times, still more preferably 1 to 5 times.

The preservative of the present invention may be used in combination with other preservatives in order to further exert the preservative effect. "Use in combination" means containing the preservative of the present invention and another preservative in one pharmaceutical composition. Examples of other preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzyl dodecinium bromide, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, Examples thereof include cyclohexidine, boric acid or a salt thereof, edetic acid or a salt thereof, and the like. Examples of salts of boric acid include borax, sodium borate, potassium borate and the like. Examples of salts of edetic acid include monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, disodium edetate is preferred, and disodium edetate dihydrate is particularly preferred. ..
In the pharmaceutical composition in which the antiseptic of the present invention is used, the content of the other antiseptic used in combination is not particularly limited as long as it is an amount sufficient to achieve the desired antiseptic effect, but 0.00001 -0.5% (w/v) is preferable, 0.00005-0.1% (w/v) is more preferable, 0.0001-0.05% (w/v) is further preferable, 0.0005 -0.01% (w/v) is still more preferable, and 0.0007-0.005% (w/v) is especially preferable. More specifically, in the case of benzalkonium chloride, 0.0001 to 0.001% (w/v) is preferable, 0.0002 to 0.0008% (w/v) is more preferable, and 0. 0003 to 0.0007% (w/v) is particularly preferable, and 0.0004 to 0.0006% (w/v) is most preferable. In the case of boric acid and its salts, it is preferable that the total content thereof is not more than 0.5% (w/v) (the content is less than 0.5% (w/v)), and 0.00001 is preferable. -0.1% (w/v) is preferable, 0.00005-0.05% (w/v) is more preferable, 0.0001-0.01% (w/v) is further preferable, 0.0005 Is more preferably 0.005% (w/v), most preferably 0.0007 to 0.001% (w/v). When a boric acid salt is contained in the pharmaceutical composition of the present invention, these values are the contents converted into free boric acid. In the case of edetic acid or a salt thereof, the total content thereof is preferably 0.00001 to 0.5% (w/v), more preferably 0.00005 to 0.3% (w/v), and 0. 0.0001-0.1% (w/v) is more preferable, 0.0005-0.08% (w/v) is still more preferable, 0.001-0.05% (w/v) is further preferable. , 0.005-0.03% (w/v) is particularly preferable, and 0.007-0.01% (w/v) is most preferable. When the pharmaceutical composition of the present invention contains a salt of edetic acid or a hydrate thereof, these values are contents calculated based on the mass of the salt of edetic acid or a hydrate thereof.

As described above, the antiseptic of the present invention may be used in combination with other antiseptics, while the above antiseptic of the present invention (Dorzolamide or a salt thereof) alone exhibits sufficient antiseptic effect. The pharmaceutical composition of the present invention does not contain an antiseptic agent other than the above-described antiseptic agent of the present invention or can be contained in a predetermined amount. Here, the "predetermined amount" means, for example, an amount that does not exert a sufficient antiseptic effect alone, and specifically, in a test sample consisting of an antiseptic and water, ATCC of Escherichia coli is used. After inoculating the bacteria so that the concentration of the bacterial solution of 8739 is within the range of 10 ⁵ to 10 ⁶ cfu/mL and mixing them uniformly, the test sample was stored at 20 to 25° C. in the dark and after 7 days had elapsed. , The common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured was 2.0 or less. The amount is preferably 1.5 or less, more preferably 1.2 or less, further preferably 1.0 or less, more preferably 0.8 or less, still more preferably 0.7 or less, particularly preferably 0. The amount is 5 or less, and most preferably 0.3 or less. Alternatively, the “predetermined amount” means, for example, that the bacterial solution concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing a preservative and water. When 28 days have passed since the test sample was inoculated and mixed uniformly and stored at 20 to 25°C under light shielding, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The amount (B/A) of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) is 4.0 or less, preferably 3.5 or less, and more preferably 3.2. The amount is preferably 3.0 or less, more preferably 3.0 or less, more preferably 2.8 or less, still more preferably 2.6 or less, particularly preferably 2.4 or less, and most preferably 2.0 or less. These "predetermined amounts" vary depending on the type of preservative, but are preferably 0.001% (w/v) or less, more preferably 0.0007% (w/v) or less, and 0.0005% ( w/v) or less is more preferable, 0.0003% (w/v) or less is more preferable, 0.0001% (w/v) or less is particularly preferable, and it is most preferable that it is not substantially contained.

In particular, in the pharmaceutical composition of the present invention, it is desirable that the content of benzalkonium chloride as a preservative is small or not contained. When the pharmaceutical composition of the present invention contains benzalkonium chloride, it is preferable that benzalkonium chloride is contained in a predetermined amount. Here, the "predetermined amount" means, for example, an amount that does not exert a sufficient antiseptic effect alone, and specifically, in a test sample consisting of an antiseptic and water, ATCC of Escherichia coli is used. After inoculating the bacteria so that the concentration of the bacterial solution of 8739 is within the range of 10 ⁵ to 10 ⁶ cfu/mL and mixing them uniformly, the test sample was stored at 20 to 25° C. in the dark and after 7 days had elapsed. , The common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured was 2.0 or less. The amount is preferably 1.5 or less, more preferably 1.2 or less, further preferably 1.0 or less, more preferably 0.8 or less, still more preferably 0.7 or less, particularly preferably 0. The amount is 5 or less, and most preferably 0.3 or less. Alternatively, the “predetermined amount” means, for example, that the bacterial solution concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing a preservative and water. When 28 days have passed since the test sample was inoculated and mixed uniformly and stored at 20 to 25°C under light shielding, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The amount (B/A) of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) is 4.0 or less, preferably 3.5 or less, and more preferably 3.2. The amount is preferably 3.0 or less, more preferably 3.0 or less, more preferably 2.8 or less, still more preferably 2.6 or less, particularly preferably 2.4 or less, and most preferably 2.0 or less. More specifically, these “predetermined amounts” of benzalkonium chloride are preferably 0.001% (w/v) or less, more preferably 0.0007% (w/v) or less, and 0.0005% or less. % (W/v) or less is more preferable, 0.0003% (w/v) or less is more preferable, 0.0001% (w/v) or less is particularly preferable, and substantially not contained is most preferable. Further, it is desirable that the content of the quaternary ammonium salt used as a preservative other than benzalkonium chloride is small or not contained. Examples of the quaternary ammonium salt other than benzalkonium chloride include benzalkonium bromide, benzethonium chloride, benzyldodecinium bromide and the like. When the pharmaceutical composition of the present invention contains a quaternary ammonium salt other than benzalkonium chloride, the quaternary ammonium salt is preferably contained in a predetermined amount. Here, the "predetermined amount" means, for example, an amount that does not exert a sufficient antiseptic effect alone, and specifically, in a test sample consisting of an antiseptic and water, ATCC of Escherichia coli is used. After inoculating the bacteria so that the concentration of the bacterial solution of 8739 is within the range of 10 ⁵ to 10 ⁶ cfu/mL and mixing them uniformly, the test sample was stored at 20 to 25° C. in the dark and after 7 days had elapsed. , The common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured was 2.0 or less. The amount is preferably 1.5 or less, more preferably 1.2 or less, further preferably 1.0 or less, more preferably 0.8 or less, still more preferably 0.7 or less, particularly preferably 0. The amount is 5 or less, and most preferably 0.3 or less. Alternatively, the “predetermined amount” means, for example, that the bacterial solution concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing a preservative and water. When 28 days have passed since the test sample was inoculated and mixed uniformly and stored at 20 to 25°C under light shielding, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The amount (B/A) of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) is 4.0 or less, preferably 3.5 or less, and more preferably 3.2. The amount is preferably 3.0 or less, more preferably 3.0 or less, more preferably 2.8 or less, still more preferably 2.6 or less, particularly preferably 2.4 or less, and most preferably 2.0 or less. These “predetermined amounts” vary depending on the type of quaternary ammonium, but for example, quaternary ammonium salts other than benzalkonium chloride are not contained in an amount of 0.01% (w/v) or more (content 0.01 % (W/v)), preferably 0.005% (w/v) or more, more preferably 0.001% (w/v) or more, and even more preferably 0.00. It is more preferable that it is not contained in an amount of 0005% (w/v) or more, particularly preferably 0.0001% (w/v) or more, and most preferably substantially not contained.

In the pharmaceutical composition of the present invention, it is desirable that the content of preservatives other than quaternary ammonium salts (excluding dorzolamide and its salts) is small or not contained. Preservatives other than quaternary ammonium salts include sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, cyclohexidine, polyhexamethylene biguanide, boric acid or its salts, edetic acid or its salts. , N-hexadecanyl-DABCO (1,4-diazabicyclo[2.2.2]octane) and the like. When the pharmaceutical composition of the present invention contains a preservative other than the quaternary ammonium salt, the preservative is preferably contained in a predetermined amount. Here, the "predetermined amount" means, for example, an amount that does not exert a sufficient antiseptic effect alone, and specifically, in a test sample consisting of an antiseptic and water, ATCC of Escherichia coli is used. After inoculating the bacteria so that the concentration of the bacterial solution of 8739 is within the range of 10 ⁵ to 10 ⁶ cfu/mL and mixing them uniformly, the test sample was stored at 20 to 25° C. in the dark and after 7 days had elapsed. , The common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured was 2.0 or less. The amount is preferably 1.5 or less, more preferably 1.2 or less, further preferably 1.0 or less, more preferably 0.8 or less, still more preferably 0.7 or less, particularly preferably 0. The amount is 5 or less, and most preferably 0.3 or less. Alternatively, the “predetermined amount” means, for example, that the bacterial solution concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing a preservative and water. When 28 days have passed since the test sample was inoculated and mixed uniformly and stored at 20 to 25°C under light shielding, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The amount (B/A) of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) is 4.0 or less, preferably 3.5 or less, and more preferably 3.2. The amount is preferably 3.0 or less, more preferably 3.0 or less, more preferably 2.8 or less, still more preferably 2.6 or less, particularly preferably 2.4 or less, and most preferably 2.0 or less. These "predetermined amounts" vary depending on the types of components of the preservatives other than the quaternary ammonium salt, but, for example, preservatives other than the quaternary ammonium salt are not contained in 0.5% (w/v) or more ( The content is preferably less than 0.5% (w/v), and more preferably 0.10% (w/v) or more (the content is less than 0.10% (w/v)). , 0.05% (w/v) or more is more preferable, 0.01% (w/v) or more is not preferable, 0.005% (w/v) or more is not contained. It is more preferable that 0.001% (w/v) or more is not contained, and it is most preferable that it is substantially not contained. In particular, when the preservative other than the quaternary ammonium salt is boric acid or its salt, boric acid and its salt are not contained in an amount of 0.5% (w/v) or more (the content is 0.5% (w Less than 0.10% (w/v), more preferably not more than 0.10% (w/v) (content is less than 0.10% (w/v)), more preferably 0.05% (w/v). ) Or more, more preferably not more than 0.03% (w/v), even more preferably not more than 0.01% (w/v), even more preferably not more than 0.005 % (W/v) or more is more preferable, 0.001% (w/v) or more is particularly preferable, and substantially not contained is most preferable. Examples of salts of boric acid include borax, sodium borate, potassium borate and the like. When a boric acid salt is contained in the pharmaceutical composition of the present invention, these values are the contents converted into free boric acid. Further, edetic acid or a salt thereof is often added to a pharmaceutical composition as a stabilizer, but it is also known that these have an antiseptic effect, and the pharmaceutical composition of the present invention contains edetic acid or a salt thereof. When included, the total content is more than 0% (w/v) (0.0001% or more, 0.0005% or more, 0.001% or more, 0.002% or more, 0.003% or more, 0 or more. 0.005% or more, 0.007% or more) 0.5% (w/v) or less is preferable, 0.3% (w/v) or less is more preferable, and 0.1% (w/v) or less is preferable. More preferably, 0.08% (w/v) or less is more preferable, 0.05% (w/v) or less is still more preferable, 0.03% (w/v) or less is particularly preferable, and 0.01%( Most preferred is w/v) or less. Examples of salts of edetic acid include monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, disodium edetate is preferred, and disodium edetate dihydrate is particularly preferred. .. In particular, the pharmaceutical composition of the present invention preferably contains no preservatives (excluding dorzolamide and salts thereof) other than edetic acid and salts thereof. Alternatively, when the pharmaceutical composition of the present invention contains a preservative other than edetic acid and its salt, the preservative is preferably contained in a predetermined amount. Here, the "predetermined amount" means, for example, an amount that does not exert a sufficient antiseptic effect alone, and specifically, in a test sample consisting of an antiseptic and water, ATCC of Escherichia coli is used. After inoculating the bacteria so that the concentration of the bacterial solution of 8739 is within the range of 10 ⁵ to 10 ⁶ cfu/mL and mixing them uniformly, the test sample was stored at 20 to 25° C. in the dark and after 7 days had elapsed. , The common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured was 2.0 or less. The amount is preferably 1.5 or less, more preferably 1.2 or less, further preferably 1.0 or less, more preferably 0.8 or less, still more preferably 0.7 or less, particularly preferably 0. The amount is 5 or less, and most preferably 0.3 or less. Alternatively, the “predetermined amount” means, for example, that the bacterial solution concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing a preservative and water. When 28 days have passed since the test sample was inoculated and mixed uniformly and stored at 20 to 25°C under light shielding, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The amount (B/A) of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) is 4.0 or less, preferably 3.5 or less, and more preferably 3.2. The amount is preferably 3.0 or less, more preferably 3.0 or less, more preferably 2.8 or less, still more preferably 2.6 or less, particularly preferably 2.4 or less, and most preferably 2.0 or less. Alternatively, the pharmaceutical composition of the present invention preferably contains no preservatives (excluding dorzolamide and its salts) other than edetic acid and its salts and benzalkonium chloride. Alternatively, when the pharmaceutical composition of the present invention contains a preservative other than edetic acid and a salt thereof and benzalkonium chloride, the preservative is preferably contained in a predetermined amount. Here, the “predetermined amount” refers to, for example, an amount that does not exert a sufficient antiseptic effect alone, and specifically, in a test sample containing an antiseptic and water, ATCC of Escherichia coli is used. After inoculating the bacteria so that the concentration of the bacterial solution of 8739 is within the range of 10 ⁵ to 10 ⁶ cfu/mL and mixing them uniformly, the test sample was stored at 20 to 25° C. in the dark and after 7 days had elapsed. , 1 mL of the test sample was taken with a micropipette and the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the viable cell count was measured was 2.0 or less. The amount is preferably 1.5 or less, more preferably 1.2 or less, further preferably 1.0 or less, more preferably 0.8 or less, still more preferably 0.7 or less, and particularly preferably 0. The amount is 5 or less, and most preferably 0.3 or less. Alternatively, the “predetermined amount” means, for example, that the concentration of the bacterial solution of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing a preservative and water. When 28 days have passed since the test sample was stored at 20 to 25°C in the dark after being inoculated with the bacteria and uniformly mixed with the test sample, 1 mL of the test sample was sampled with a micropipette and the viable cell count was measured. The amount (B/A) of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) is 4.0 or less, preferably 3.5 or less, more preferably 3.2. The amount is preferably 3.0 or less, more preferably 3.0 or less, more preferably 2.8 or less, still more preferably 2.6 or less, particularly preferably 2.4 or less, and most preferably 2.0 or less. When the pharmaceutical composition of the present invention contains a salt of edetic acid or a hydrate thereof, these values are contents calculated based on the mass of the salt of edetic acid or a hydrate thereof. Further, in the present invention, the preservatives other than dorzolamide or a salt thereof refer to a component described as a preservative in the pharmaceutical composition, and the active ingredient itself of the drug in the pharmaceutical composition of the present invention has an antiseptic effect It does not include components not indicated as agents.

Preservatives preferably not included in the above-mentioned pharmaceutical composition of the present invention or preservatives preferably contained in a predetermined amount are benzalkonium chloride, quaternary ammonium salts other than benzalkonium chloride, boric acid or boric acid thereof. It is salt. The preservatives preferably not contained in the pharmaceutical composition or the preservatives preferably contained in a predetermined amount may be one kind alone or two or more kinds.

In the pharmaceutical composition in which the preservative of the present invention is used, additives can be used if necessary, and the additives include surfactants, buffering agents, isotonicity agents, stabilizers, Oxidizing agents, high molecular weight polymers and the like can be added.

The pharmaceutical composition in which the preservative of the present invention is used should be mixed with a surfactant that can be used as an additive for pharmaceuticals, such as a cationic surfactant, an anionic surfactant, or a nonionic surfactant. You can
Examples of the anionic surfactant include phospholipids and the like, and examples of the phospholipids include lecithin and the like.
Examples of the cationic surfactant include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl- Examples thereof include 2-alkylimidazoline and 1-hydroxylethyl-2-alkylimidazoline.
Examples of the nonionic surfactant, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, Vitamin E TPGS etc. are mentioned.

Examples of the polyoxyethylene fatty acid ester include polyoxyl 40 stearate.

Examples of the polyoxyethylene sorbitan fatty acid ester include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 and the like.

As the polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, and 40 ~70 is particularly preferred, and 60 is most preferred. Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 and the like.

As the polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, and 30 to 40. Is particularly preferable, and 35 is the most preferable. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like.

As polyoxyethylene polyoxypropylene glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) Examples thereof include glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, and the like.

Examples of the sucrose fatty acid ester include sucrose stearate and the like.

Vitamin E TPGS is also called tocopherol polyethylene glycol 1000 succinate.

The content of the surfactant when the surfactant is added to the pharmaceutical composition in which the antiseptic of the present invention is used can be appropriately adjusted depending on the kind of the surfactant and the like, but is 0.001 to 10%. (W/v) is preferred, 0.01-5% (w/v) is more preferred, 0.1-3% (w/v) is even more preferred, and 0.2-2% (w/v) is preferred. Most preferred.

The pharmaceutical composition in which the preservative of the present invention is used can be mixed with a buffering agent that can be used as an additive for pharmaceuticals. Examples of the buffer include phosphoric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol and the like.
Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the like. Sodium, disodium citrate and the like, as the acetate, sodium acetate, potassium acetate and the like, as the carbonate, sodium carbonate, sodium hydrogencarbonate and the like, tartrate, sodium tartrate, Examples thereof include potassium tartrate. Citric acid or a salt thereof is preferable, and sodium citrate is particularly preferable.

The content of the buffer when the buffer is mixed in the pharmaceutical composition in which the preservative of the present invention is used can be appropriately adjusted depending on the type of the buffer and the like, but 0.001 to 10% (w/ v) is preferable, 0.01-5% (w/v) is more preferable, 0.1-3% (w/v) is further preferable, and 0.2-2% (w/v) is the most preferable.

An isotonicity agent that can be used as an additive for pharmaceuticals can be appropriately added to the pharmaceutical composition in which the preservative of the present invention is used. Examples of the tonicity agent include an ionic tonicity agent and a nonionic tonicity agent. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like, with sodium chloride being preferred. Examples of the nonionic tonicity agent include glycerin, propylene glycol, sorbitol, mannitol and the like, and mannitol is preferable. The content of the isotonicity agent when blending the isotonicity agent in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of isotonicity agent and the like, but is 0.01 to 10% (w/ v) is preferable, 0.02 to 7% (w/v) is more preferable, 0.1 to 5% (w/v) is further preferable, 0.5 to 4% (w/v) is particularly preferable, Most preferred is 0.8-3% (w/v).

The pharmaceutical composition in which the antiseptic of the present invention is used can be appropriately mixed with a stabilizer that can be used as an additive for pharmaceuticals. Examples of stabilizers include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, disodium edetate is preferred, and disodium edetate dihydrate is used. Particularly preferred. The content of the stabilizer when the stabilizer is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the stabilizer and the like, but 0.0001 to 0.5% (w/v ) Is preferable, 0.0005 to 0.3% (w/v) is more preferable, 0.001 to 0.1% (w/v) is further preferable, and 0.002 to 0.08% (w/v). ) Is more preferable, 0.003 to 0.05% (w/v) is further preferable, 0.005 to 0.03% (w/v) is particularly preferable, and 0.007 to 0.01% (w/v). v) is most preferred.

The pharmaceutical composition in which the antiseptic agent of the present invention is used can be appropriately mixed with an antioxidant that can be used as an additive for pharmaceuticals. Examples of antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like. The content of the antioxidant in the case of adding the antioxidant to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant and the like, but 0.0001 to 1% (w/v) is used. 0.0005 to 0.1% (w/v) is more preferable, 0.001 to 0.02% (w/v) is further preferable, and 0.005 to 0.010% (w/v) is preferable. Most preferred.

The pharmaceutical composition in which the preservative of the present invention is used can be appropriately blended with a high molecular weight polymer that can be used as an additive for pharmaceuticals. Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxy vinyl polymer, polyethylene glycol and the like can be mentioned, with hydroxy ethyl cellulose being preferred. When the high molecular weight polymer is added to the pharmaceutical composition of the present invention, the content of the high molecular weight polymer can be appropriately adjusted depending on the kind of the high molecular weight polymer and the like, but 0.001 to 5% (w/ v) is preferable, 0.01-3% (w/v) is more preferable, 0.1-2% (w/v) is further preferable, and 0.2-1% (w/v) is the most preferable.

The pharmaceutical composition in which the preservative of the present invention is used can be appropriately mixed with a pH adjuster that can be used as an additive for pharmaceuticals. Examples of the pH adjusting agent include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like, and citric acid is preferable.

The pharmaceutical composition in which the preservative of the present invention is used can be appropriately mixed with active ingredients of usable pharmaceutical products, but the active ingredients may not be blended. Examples of active ingredients include α ₂ receptor agonists such as brimonidine, β-receptor blockers such as befnolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, isopropylunoprostone, latanoprost, travoprost, bimatoprost. Prostaglandin derivatives and the like.

The pH of the pharmaceutical composition in which the preservative of the present invention is used is preferably 4.0 to 8.0, more preferably 5.0 to 7.5, still more preferably 5.5 to 7.3. 5-7.0 is more preferable, 5.5-6.8 is especially preferable, and 6.0-6.8 is the most preferable.

The pharmaceutical composition in which the preservative of the present invention is used is preferably placed in a container that can be used repeatedly, and examples of the container that can be used repeatedly include a multidose type container and a recap unit dose container. The multi-dose type container is a container in which a cap or the like can be freely opened and closed for the purpose of being used a plurality of times. However, a PFMD (Preservative Free Multi Dose) container having a special structure for exhibiting an antiseptic effect such as a backflow prevention function is not included. The recap unit dose container is a unit dose container that can be repeatedly used by recapping. The material of the container is not particularly limited, and for example, a container made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET) or the like can be used.

The dosage form of the pharmaceutical composition in which the antiseptic of the present invention is used is not particularly limited as long as it can be used as a medicine, but eye drops are particularly preferable, and it can be produced according to a usual method in the technical field. ..

The pharmaceutical composition in which the preservative of the present invention is used is also useful as a therapeutic agent for glaucoma or ocular hypertension, because the used dorzolamide or its salt is a carbonic anhydrase inhibitor and has an intraocular pressure lowering action. .. In this case, dorzolamide or its salt is used as an antiseptic, for example, it is used to meet the criteria “Category IA” according to the 16th revised Japanese Pharmacopoeia reference information “Preservation efficacy test method”. As long as it is provided, it may be contained in the pharmaceutical composition as an active ingredient (API) of a therapeutic agent for glaucoma or ocular hypertension.

When administering a pharmaceutical composition in which the antiseptic of the present invention is used, the dosage is not particularly limited as long as it is sufficient to achieve the desired drug effect, but 1 to 3 drops once, 1 to 5 times daily Instillation is preferable, 1-2 drops once a day, more preferably 2 to 4 times a day, more preferably 1 drop once a day, and most preferably 3 times a day.

The pharmaceutical composition of the present invention is useful for contact lenses (wearers). The type of contact lens to be applied is not particularly limited, and specific examples thereof include hard contact lenses and soft contact lenses, and oxygen permeable contact lenses may be used. Examples of soft contact lenses include hydrous soft contact lenses, non-hydrous soft contact lenses, and (nonionic) silicone hydrogel soft contact lenses.

The above detailed description of the preservative of the present invention and the pharmaceutical composition in which the preservative of the present invention is used, the product comprising the container (containing the pharmaceutical composition) of the pharmaceutical composition of the present invention can be repeatedly used, Also, it is applied to a method for improving the antiseptic effect.

The method for improving the antiseptic effect of the present invention is that it does not contain benzalkonium chloride, does not contain boric acid or its salt, or has a boric acid or its salt content of less than 0.001% (w/v). It is preferable that the method is to further improve the antiseptic effect by further containing dorzolamide or a salt thereof in the pharmaceutical composition contained in a container that can be used repeatedly.

Alternatively, the method for improving the antiseptic effect of the present invention is to contain dorzolamide or a salt thereof in a medicinal composition containing no preservative or containing a predetermined amount in a reusable container and further containing dorzolamide or a salt thereof. The method of improving the antiseptic effect is preferable. Here, the "preservative" and "predetermined amount" in the method of improving the antiseptic effect of the present invention may be the same as those described in the above antiseptic of the present invention and the pharmaceutical composition of the present invention. .. Particularly, preservatives preferably not contained in the pharmaceutical composition or preservatives preferably contained in a predetermined amount are boric acid and salts thereof, benzalkonium chloride, and quaternary ammonium salts other than benzalkonium chloride. Is. Among these, the preservatives that are preferably not contained or the preservatives that are preferably contained in a predetermined amount may be one kind or two or more kinds.

The method for improving the antiseptic effect of the present invention is such that the pharmaceutical composition before containing dorzolamide or a salt thereof has a bacterial solution concentration of Escherichia coli of ATCC 8739 of 10 ⁵ to 10 ⁶ After inoculating the bacteria so as to be within the range of cfu/mL, mixing them uniformly, and storing the pharmaceutical composition at 20 to 25° C. in the dark, after 7 days, 1 mL of the pharmaceutical composition was applied with a micropipette. It is preferable that the common logarithm of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) at the time of collecting and measuring the number of viable bacteria is 2.0 or less, and 1.5 It is more preferably at most 1.0, even more preferably at most 1.0, even more preferably at most 0.7, particularly preferably at most 0.5, most preferably at most 0.3. preferable.

The method for improving the antiseptic effect of the present invention is such that the pharmaceutical composition before containing dorzolamide or a salt thereof has a bacterial solution concentration of Escherichia coli of ATCC 8739 of 10 ⁵ to 10 ⁶ After inoculating the bacteria so as to be in the range of cfu/mL, mixing them uniformly, and storing the pharmaceutical composition at 20 to 25° C. under light-shielding, after 28 days, 1 mL of the pharmaceutical composition was pipetted with a micropipette. The common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) at the time of collecting and measuring the number of viable bacteria is preferably 4.0 or less, 3.5 It is more preferable that it is not more than 3.2, it is more preferable that it is not more than 3.2, it is more preferable that it is not more than 3.0, it is more preferable that it is not more than 2.8, and it is particularly preferable that it is not more than 2.6 Most preferably, it is 2.4 or less, and most preferably 2.0 or less.

In the method for improving the antiseptic effect of the present invention, the pharmaceutical composition after containing the above-mentioned dorzolamide or a salt thereof has a bacterial solution concentration of ATCC 8739 of Escherichia coli of 10 ⁵ After inoculating the bacteria so as to be in the range of 10 ⁶ cfu/mL and mixing them evenly, and storing the pharmaceutical composition at 20 to 25° C. in the dark, 7 days after the storage, the pharmaceutical composition was micropipetteed. It is preferable that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) at the time of measuring the viable cell count is 2.5 or more, It is more preferably 3.0 or more, further preferably 3.5 or more, and further preferably 4.0 or more. Alternatively, in the method for improving the antiseptic effect of the present invention, the pharmaceutical composition after containing the above-mentioned dorzolamide or a salt thereof has a standard “category IA” according to the 16th revised Japanese Pharmacopoeia reference information “preservation efficacy test method”. It is preferable to satisfy.

In the method for improving the antiseptic effect of the present invention, the pharmaceutical composition after containing the above-mentioned dorzolamide or a salt thereof has a bacterial solution concentration of ATCC 8739 of Escherichia coli of 10 ⁵ After inoculating the bacteria so as to be within the range of 10 ⁶ cfu/mL and mixing them uniformly, and storing the pharmaceutical composition at 20 to 25° C. under light shielding, 28 days after the pharmaceutical composition, the pharmaceutical composition is micropipette. It is preferable that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) at the time of measuring the viable cell count is 3.0 or more, It is more preferably 3.5 or more, still more preferably 4.0 or more, and further preferably 4.5 or more. Alternatively, in the method for improving the antiseptic effect of the present invention, the pharmaceutical composition after containing the above-mentioned dorzolamide or a salt thereof has a standard “category IA” according to the 16th revised Japanese Pharmacopoeia reference information “preservation efficacy test method”. It is preferable to satisfy.

Formulation examples and the results of the antiseptic efficacy test are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

Formulation Example A typical formulation example of the present invention is shown below. In addition, in the following formulation examples, the compounding amount of each component is the content in 1 mL of the formulation.

Formulation Example 1 (in a multi-dose container)
Dorzolamide 10 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Formulation example 2 (in a multi-dose container)
Dorzolamide 20mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

The desired composition can be obtained by appropriately adjusting the types and blending amounts of Dorzolamide, Timolol and the additives in Formulation Examples 1 and 2.

Antiseptic test (1)
1. Preparation of test preparation Dorzolamide hydrochloride (22.26 mg), timolol maleate (6.83 mg), sodium citrate (2.94 mg) and mannitol (16 mg) were dissolved in water and sterilized by filtration, and Separately, hydroxyethyl cellulose (4.75 mg) was dissolved in water and subjected to high-pressure steam sterilization, and liquid B was mixed and adjusted to pH 5.7 with a pH adjuster, and then water was added to bring the total volume to 1 mL. The formulation of Example 1 was prepared. Example 2 and Comparative Examples 1-2 were prepared in the same manner as Example 1.

Example 1 (in 1 mL)
Dorzolamide hydrochloride 22.26 mg
Timolol maleate 6.83mg
Sodium citrate hydrate 2.94 mg
Mannitol 16mg
Hydroxyethyl cellulose 4.75 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.7

The preparations of Examples 2 to 3 and Comparative Example 1 shown in Table 1 were prepared in the same manner as the preparation method of Example 1.

Example 2 (in 1 mL)
Dorzolamide hydrochloride 11.13 mg
Timolol maleate 6.83mg
Sodium citrate hydrate 2.94 mg
Mannitol 30mg
Hydroxyethyl cellulose 4.75 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.7

Example 3 (in 1 mL)
Dorzolamide hydrochloride 11.13 mg
Sodium citrate hydrate 2.94 mg
Mannitol 30mg
Hydroxyethyl cellulose 4.75 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.7

Comparative Example 1 (in 1 mL)
Timolol maleate 6.83mg
Sodium citrate hydrate 2.94 mg
Mannitol 30mg
Hydroxyethyl cellulose 4.75 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.8

2. Test method The following strains were used as inoculum.
Bacteria:
E. coli, Escherichia Coli ATCC 8739 (also called E.coli)
Pseudomonas aeruginosa ATCC 9027 (also called P. aeruginosa)
Staphylococcus aureus ATCC 6538 (also called S. aureus)
Yeasts and molds:
Candida albicans ATCC 10231 (also called C. albicans)
Aspergillus brasiliensis ATCC16404 (A. brasiliensis
Also say)

The test sample was inoculated with the inoculum bacterial solution so that the concentration of the bacterial solution in the test sample consisting of each preparation was 10 ⁵ to 10 ⁶ cells/mL (for 5 bacterial species). Specifically, the inoculum bacterial solution was prepared so as to be 10 ⁷ to 10 ⁸ cfu/mL, and Examples 1 to 3 and Comparative Example were prepared so that the inoculum bacterial solution became 10 ⁵ to 10 ⁶ cfu/mL. A test sample consisting of the preparation 1 was inoculated with each inoculum bacterial solution and uniformly mixed to obtain a sample. These samples were stored at 20 to 25° C. in the dark, and at each sampling point (6 hours, 24 hours, 7 days, 14 days, or 28 days later), 1 mL was collected from each sample with a micropipette, and live cells were collected. The number was measured. At each sampling point, the lid of the sample solution was opened for sampling, and the lid was closed.

3. Test results and discussion Table 1 shows the test results. The test results in Table 1 are shown as a common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured, for example, "1". In some cases, the viable cell count at the time of inspection was reduced to 10% of the inoculated cell count.

As shown in Table 1, the formulations of Examples 1 to 3 containing dorzolamide or a salt thereof showed an antiseptic effect against all the bacteria. On the other hand, the formulation of Comparative Example 1 containing no dorzolamide or a salt thereof was inferior in antiseptic effect, and particularly was weak in antiseptic effect against Escherichia coli. Thereby, the antiseptic of the present invention shows an excellent antiseptic effect against a wide variety of fungal species, can be put in a multi-dose type container, and can sufficiently exhibit the antiseptic effect even when repeatedly used by opening and closing the container. It was suggested. Further, the preparations of Examples 1 and 2, which further contained timolol or a salt thereof in addition to dorzolamide or a salt thereof, showed a particularly excellent antiseptic effect.

Antiseptic test (2)
1. Preparation of Test Preparations The preparations of Examples 4 to 7 were prepared by the same method as the preparation method of Example 1.

Example 4 (in 1 mL)
Dorzolamide hydrochloride 11.13 mg
Timolol maleate 6.83mg
Sodium chloride 9mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65

Example 5 (in 1 mL)
Dorzolamide hydrochloride 11.13 mg
Timolol maleate 6.83mg
Sodium chloride 9mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5

Example 6 (in 1 mL)
Dorzolamide hydrochloride 11.13 mg
Timolol maleate 6.83mg
Sodium citrate hydrate 2.94 mg
Mannitol 30mg
Hydroxyethyl cellulose 4.75 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65

Example 7 (in 1 mL)
Dorzolamide hydrochloride 11.13 mg
Timolol maleate 6.83mg
Sodium citrate hydrate 2.94 mg
Mannitol 30mg
Hydroxyethyl cellulose 4.75 mg
Disodium edetate dihydrate 0.5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65

2. Test method 2. Preservative efficacy test (1) 2. A preservative efficacy test was carried out by the same method as the test method. However, the sampling points were 7 days, 14 days, or 28 days later.

3. Test results and discussion Table 2 shows the test results. The test results in Table 2 are shown as the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured.

As shown in Table 2, the formulations of Examples 4 to 7 containing dorzolamide or a salt thereof showed an antiseptic effect against all the bacteria, although they did not contain benzalkonium chloride. Thereby, the antiseptic of the present invention shows an excellent antiseptic effect against a wide variety of fungal species, can be put in a multi-dose type container, and can sufficiently exhibit the antiseptic effect even when repeatedly used by opening and closing the container. It was suggested.

Antiseptic test (3)
1. Preparation of Test Preparations The preparations of Comparative Examples 2 and 3 were prepared in the same manner as the preparation method of Example 1.

Comparative example 2 (in 1 mL)
Timolol maleate 6.83mg
Sodium citrate hydrate 2.94 mg
Hydroxyethyl cellulose 4.75 mg
Disodium edetate dihydrate 0.5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65

Comparative Example 3 (in 1 mL)
Sodium citrate hydrate 2.94 mg
Hydroxyethyl cellulose 4.75 mg
Disodium edetate dihydrate 0.5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65

2. Test method 2. Preservative efficacy test (1) 2. A preservative efficacy test was carried out by the same method as the test method. However, the sampling point was 7 days later.

3. Test results and discussion Table 3 shows the test results. The test results in Table 3 are shown by the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured.

As shown in Table 3, the preparations of Comparative Examples 2 and 3 containing edetate disodium dihydrate, which is known to have some antiseptic effect, and not containing dorzolamide or a salt thereof, were dorzolamide or its preparation. The antiseptic effect was particularly weak against Escherichia coli and Staphylococcus aureus as compared with the formulation of Example 7 containing salt.

Claims (12)

A preservative containing dorzolamide or a salt thereof. Preservative according to claim 1, for a pharmaceutical composition to be placed in a multidose container. Preservative according to claim 1 or 2 for a pharmaceutical composition free of benzalkonium chloride. Preservative according to any one of claims 1 to 3 for a pharmaceutical composition which does not contain boric acid or its salts. The preservative according to any one of claims 1 to 4, wherein the dorzolamide or a salt thereof is dorzolamide hydrochloride. The preservative according to any one of claims 1 to 5, which is used in combination with edetic acid or a salt thereof. The preservative according to claim 6, wherein the salt of edetic acid is monosodium edetate, disodium edetate, tetrasodium edetate or disodium edetate dihydrate. Contain a preservative according to any one of claims 1-7, wherein not such preserving agents other than preservative, placed in repetitive usable container, the pharmaceutical compositions. A pharmaceutical composition containing the preservative according to any one of claims 1 to 7, which does not contain any preservative other than the preservative and edetic acid and a salt thereof,
Containing 0.0001 to 0.1% (w/v) of edetic acid or a salt thereof,
A pharmaceutical composition in a reusable container. The pharmaceutical composition according to claim 8 or 9 , wherein the content of dorzolamide or a salt thereof is 0.1-5% (w/v). The pharmaceutical composition according to any one of claims 8 to 10 , which contains dorzolamide or a salt thereof as an active ingredient of a medicine. Product comprising a pharmaceutical composition according a container which can be used repeatedly, to any one of claims 8-11.