JP6707365B2 - Combination of medicines with antiseptic effect - Google Patents

Description

The present invention relates to a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof.

Dorzolamide, which is a carbonic anhydrase inhibitor, and timolol, which is a β-receptor blocker, have been used as therapeutic agents for glaucoma or ocular hypertension because they both exhibit intraocular pressure lowering action. Furthermore, 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 both of them is sold as a Cosopt (registered trademark) eye drop solution. Has been done.

By the way, the ophthalmic solution needs to have a certain antiseptic effect in order to prevent the propagation of fungi and the like due to repeated use. Therefore, the above-mentioned Cosopt (registered trademark) ophthalmic solution contains benzalkonium as an antiseptic. Contains chloride. 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, but it does not contain a preservative. A single-use unit dose container or a PFMD (Preservative Free Multi Dose) container is used. In other words, it has been recognized that an eye drop containing both dorzolamide and timolol must contain a benzalkonium chloride or have a container structure to ensure an antiseptic effect for repeated use.

Patent Document 2 describes a composition containing dorzolamide and timolol and exhibiting an antiseptic effect without containing benzalkonium chloride. However, it is clearly stated that the composition containing timolol does not exhibit an antiseptic effect unless it contains a certain amount of boric acid.

From the viewpoints of convenience, safety, manufacturing cost, etc., a new ophthalmic solution containing benzalkonium chloride and a new dorzolamide and timolol that can be repeatedly used without using a container having a special structure is desired. There is.

Japanese Patent No. 2527513 International publication WO2011/013794 pamphlet

The subject of the present invention is a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, and provides a new pharmaceutical composition capable of sufficiently exerting an antiseptic effect even when repeatedly used by opening and closing the container. That is.

The present inventors have surprisingly found that even if a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof does not contain benzalkonium chloride, the container can be repeatedly opened and closed. It was found that the antiseptic effect can be sufficiently exhibited, and the present invention has been completed. Specifically, the present invention provides the following.

(1) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, containing no preservative or a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 2.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A pharmaceutical composition contained in a multidose container.

(2) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, containing no preservative or a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.5 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A pharmaceutical composition contained in a multidose container.

(3) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, containing no preservative or a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A pharmaceutical composition contained in a multidose container.

(4) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which does not contain benzalkonium chloride, does not contain a preservative other than benzalkonium chloride, or contains a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 2.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A pharmaceutical composition contained in a multidose container.

(5) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which does not contain benzalkonium chloride, does not contain a preservative other than benzalkonium chloride, or contains a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.5 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A pharmaceutical composition contained in a multidose container.

(6) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which does not contain benzalkonium chloride, does not contain a preservative other than benzalkonium chloride, or contains a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A pharmaceutical composition contained in a multidose container.

(7) The method according to any one of (1) to (6), which contains edetic acid or a salt thereof, and the content of edetic acid or a salt thereof is 0.0001 to 0.1% (w/v). Pharmaceutical composition.

(8) The pharmaceutical composition according to (7), wherein the content of edetic acid or its salt is 0.005 to 0.03% (w/v).

(9) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, containing no preservative other than edetic acid and its salt,
The content of the edetic acid or its salt is 0.0001 to 0.1% (w/v),
A pharmaceutical composition contained in a multidose container.

(10) The pharmaceutical composition according to (9), wherein the content of edetic acid or its salt is 0.005 to 0.03% (w/v).

(11) The salt of edetic acid is monosodium edetate, disodium edetate, tetrasodium edetate or disodium edetate dihydrate, according to any one of (7) to (10). Pharmaceutical composition.

(12) The pharmaceutical composition according to any one of (1) to (11), wherein Dorzolamide or a salt thereof is Dorzolamide hydrochloride.

(13) The pharmaceutical composition according to any one of (1) to (12), wherein timolol or its salt is timolol maleate.

(14) The pharmaceutical composition according to any one of (1) to (13), wherein the content of dorzolamide or its salt is 0.1-5% (w/v).

(15) The pharmaceutical composition according to (14), wherein the content of dorzolamide or its salt is 1% (w/v) or 2% (w/v).

(16) The pharmaceutical composition according to any one of (1) to (15), wherein the content of timolol or its salt is 0.01-2% (w/v).

(17) The pharmaceutical composition according to (16), wherein the content of timolol or its salt is 0.5% (w/v).

(18) The pharmaceutical composition according to any one of (1) to (17), which does not contain boric acid or a salt thereof.

(19) The pharmaceutical composition according to any one of (1) to (18), which further contains a high molecular weight polymer.

(20) The pharmaceutical composition according to (19), wherein the high molecular weight polymer contains hydroxyethyl cellulose.

(21) The pharmaceutical composition according to any one of (1) to (20), which further contains a nonionic tonicity agent.

(22) The pharmaceutical composition according to (21), wherein the nonionic tonicity agent contains mannitol.

(23) The pharmaceutical composition according to any one of (1) to (22), which further contains a buffering agent.

(24) The pharmaceutical composition according to (23), wherein the buffer contains citric acid or a salt thereof.

(25) The pharmaceutical composition according to any one of (1) to (24), which has a pH of 4 to 8.

(26) The pharmaceutical composition according to (25), which has a pH of 5.5 to 6.8.

(27) The pharmaceutical composition according to any one of (1) to (26), which is used for treatment of glaucoma or ocular hypertension.

(28) A product comprising the pharmaceutical composition according to any one of (1) to (27) and a multidose type container.

(29) Containing timolol or a salt thereof, containing no preservative or containing a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 2.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A method for improving preservative efficacy by further containing dorzolamide or a salt thereof in a pharmaceutical composition placed in a multidose type container.

(30) Containing timolol or a salt thereof, containing no preservative or a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.5 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A method for improving preservative effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition placed in a multi-dose type container.

(31) Containing timolol or a salt thereof, containing no preservative or containing a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A method for improving preservative effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition placed in a multi-dose type container.

(32) Containing timolol or a salt thereof, containing no benzalkonium chloride, containing no preservative other than benzalkonium chloride or containing a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 2.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A method for improving preservative effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition placed in a multi-dose type container.

(33) Containing timolol or a salt thereof, containing no benzalkonium chloride, containing no preservative other than benzalkonium chloride or containing a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.5 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A method for improving preservative effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition placed in a multi-dose type container.

(34) Containing timolol or a salt thereof, containing no benzalkonium chloride, containing no preservative other than benzalkonium chloride or containing a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.0 or less,
The content of boric acid or its salt is less than 0.001% (w/v),
A method for improving preservative effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition placed in a multi-dose type container.

(35) Containing timolol or its salt, not containing boric acid or its salt, or the content of boric acid or its salt is less than 0.001% (w/v), and it was placed in a multi-dose type container. In the pharmaceutical composition,
Furthermore, by containing dorzolamide or a salt thereof, a method for improving preservative efficacy,
The pharmaceutical composition before containing the dorzolamide or a salt thereof is prepared such that the bacterial solution concentration of ATCC 8739 of Escherichia coli is within the range of 10 ⁵ to 10 ⁶ cfu/mL. After inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25° C. in the dark from light, 7 mL of the pharmaceutical composition was taken, and 1 mL of the pharmaceutical composition was sampled with a micropipette to measure the viable cell count. The method, wherein 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 that time is 2.0 or less.

(36) It contained timolol or its salt, and did not contain boric acid or its salt, or the content of boric acid or its salt was less than 0.001% (w/v), and it was placed in a multi-dose type container. In the pharmaceutical composition,
Furthermore, by containing dorzolamide or a salt thereof, a method for improving preservative efficacy,
The pharmaceutical composition before containing the dorzolamide or a salt thereof is prepared such that the bacterial solution concentration of ATCC 8739 of Escherichia coli is within the range of 10 ⁵ to 10 ⁶ cfu/mL. After inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25° C. in the dark from light, 7 mL of the pharmaceutical composition was taken, and 1 mL of the pharmaceutical composition was sampled with a micropipette to measure the viable cell count. The method, wherein 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 that time is 1.5 or less.

(37) Containing timolol or its salt, not containing boric acid or its salt, or the content of boric acid or its salt is less than 0.001% (w/v), and it was placed in a multi-dose type container. In the pharmaceutical composition,
Furthermore, by containing dorzolamide or a salt thereof, a method for improving preservative efficacy,
The pharmaceutical composition before containing the dorzolamide or a salt thereof is prepared such that the bacterial solution concentration of ATCC 8739 of Escherichia coli is within the range of 10 ⁵ to 10 ⁶ cfu/mL. After inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25° C. in the dark from light, 7 mL of the pharmaceutical composition was taken, and 1 mL of the pharmaceutical composition was sampled with a micropipette to measure the viable cell count. The method, wherein 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 that time is 1.0 or less.

(38) It contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain boric acid or its salt, or the content of boric acid or its salt is less than 0.001% (w/v). , In a pharmaceutical composition contained in a multidose container,
Furthermore, by containing dorzolamide or a salt thereof, a method for improving preservative efficacy,
The pharmaceutical composition before containing the dorzolamide or a salt thereof is prepared such that the bacterial solution concentration of ATCC 8739 of Escherichia coli is within the range of 10 ⁵ to 10 ⁶ cfu/mL. After inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25° C. in the dark from light, 7 mL of the pharmaceutical composition was taken, and 1 mL of the pharmaceutical composition was sampled with a micropipette to measure the viable cell count. The method, wherein 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 that time is 2.0 or less.

(39) It contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain boric acid or its salt, or the content of boric acid or its salt is less than 0.001% (w/v). , In a pharmaceutical composition contained in a multidose container,
Furthermore, by containing dorzolamide or a salt thereof, a method for improving preservative efficacy,
The pharmaceutical composition before containing the dorzolamide or a salt thereof is prepared such that the bacterial solution concentration of ATCC 8739 of Escherichia coli is within the range of 10 ⁵ to 10 ⁶ cfu/mL. After inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25° C. in the dark from light, 7 mL of the pharmaceutical composition was taken, and 1 mL of the pharmaceutical composition was sampled with a micropipette to measure the viable cell count. The method, wherein 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 that time is 1.5 or less.

(40) contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain boric acid or a salt thereof, or the content of boric acid or a salt thereof is less than 0.001% (w/v) , In a pharmaceutical composition contained in a multidose container,
Furthermore, by containing dorzolamide or a salt thereof, a method for improving preservative efficacy,
The pharmaceutical composition before containing the dorzolamide or a salt thereof is prepared such that the bacterial solution concentration of ATCC 8739 of Escherichia coli is within the range of 10 ⁵ to 10 ⁶ cfu/mL. After inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25° C. in the dark from light, 7 mL of the pharmaceutical composition was taken, and 1 mL of the pharmaceutical composition was sampled with a micropipette to measure the viable cell count. The method, wherein 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 that time is 1.0 or less.

It is possible to arbitrarily select and combine two or more of the configurations (1) to (40).

According to the present invention, there is provided a new pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which can sufficiently exhibit an antiseptic effect even when repeatedly used by opening and closing the container. be able to.

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

The timolol contained in the pharmaceutical composition of the present invention has a chemical name of (2S)-1-[(1,1-Dimethylethyl)amino]-3-(4-morpholin-4-yl-1,2,5- thiadiazol-3-yloxy) propan-2-ol.

The dorzolamide and timolol contained in the pharmaceutical composition of the present invention may be salts, and there is no particular limitation as long as they are pharmaceutically acceptable salts. 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 salts with organic acids, 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 the salt with halogen ion include salts with chloride ion, bromide ion, iodide ion 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.
As salts with organic amines, 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, the monohydrochloride (dorzolamide hydrochloride) is particularly preferable, and as the salt of timolol, the monomaleate (timolol maleate) is particularly preferable.

In the pharmaceutical composition of the present invention, the contained dorzolamide, timolol and salts thereof may be in the form of hydrate or solvate.

In the pharmaceutical composition of the present invention, the content of the contained dorzolamide or a salt thereof is not particularly limited as long as it is an amount sufficient to achieve a desired medicinal effect and antiseptic effect, but 0.1 to 5% (w/ v) is preferable, 0.2 to 3% (w/v) is more preferable, 0.5 to 2% (w/v) is further preferable, and 0.7 to 1.2% (w/v) is further preferable. More preferably, 1% (w/v) is particularly preferable. Most preferred is 1% (w/v) or 2% (w/v). When the pharmaceutical composition of the present invention contains a salt of dorzolamide, 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.

In the pharmaceutical composition of the present invention, the content of timolol or a salt thereof is not particularly limited as long as it is an amount sufficient to achieve a desired drug effect, but 0.01 to 2% (w/v) is used. Preferably, 0.05 to 1% (w/v) is more preferable, 0.1 to 0.8% (w/v) is further preferable, and 0.2 to 0.7% (w/v) is even more preferable. 0.5% (w/v) is particularly preferable. 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.

From the viewpoint of therapeutic effect and antiseptic effect, the content of dorzolamide or a salt thereof is preferably 0.1 to 10 times, more preferably 0.5 to 8 times, more preferably 1 to 10 times the content of timolol or a salt thereof. It is more preferably 5 times.

In the pharmaceutical composition of the present invention, since the active ingredient of the drug, dorzolamide or its salt itself has an antiseptic effect, it may contain no antiseptic or a predetermined amount. Here, the "predetermined amount" refers to, for example, an amount that does not exert an antiseptic effect alone, and specifically, in a test sample composed of an antiseptic and water, ATCC 8739 of Escherichia coli (ESC) is used. Bacteria were inoculated so that the concentration of the bacterial liquid was within the range of 10 ⁵ to 10 ⁶ cfu/mL, and mixed uniformly, and the test sample was stored at 20 to 25° C. in the dark, and after 7 days, the test was performed. 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 may be 1.5 or less, more preferably 1.2 or less, further preferably 1.0 or less, particularly preferably 0.8 or less, and most preferably 0.7 or less. .. 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" refers to, for example, an amount that does not exert a preservative effect alone, and specifically, in a test sample composed of benzalkonium chloride 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 may be preferably 1.5 or less, more preferably 1.2 or less, still more preferably 1.0 or less, particularly preferably 0.8 or less, and most preferably 0.7 or less. More specifically, benzalkonium chloride is preferably 0.001% (w/v) or less, more preferably 0.0007% (w/v) or less, and 0.0005% (w/v) or less. More preferably, 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" refers to, for example, an amount that does not exert an antiseptic effect alone, and specifically, in a test sample containing the antiseptic (quaternary ammonium salt other than benzalkonium chloride) and water. In, the Escherichia coli ATCC 8739 was inoculated with the bacteria so that the concentration of the bacterial solution was within the range of 10 ⁵ to 10 ⁶ cfu/mL, and the mixture was uniformly mixed. After 7 days from storage at 25° C., 1 mL of the test sample was taken with a micropipette and the ratio of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the viable cell count was measured (B/ The common logarithm of A) is 2.0 or less, preferably 1.5 or less, more preferably 1.2 or less, still more preferably 1.0 or less, particularly preferably 0.8 or less, most preferably 0.7 or less. May be the amount. More specifically, it is preferable that the quaternary ammonium salt other than benzalkonium chloride is not contained in an amount of 0.01% (w/v) or more (content is less than 0.01% (w/v)). It is more preferable that 0.005% (w/v) or more is not contained, it is more preferable that 0.001% (w/v) or more is not contained, and 0.0005% (w/v) or more is not contained. Is more preferable, 0.0001% (w/v) or more is particularly preferably not contained, and substantially not contained is most preferable.

In the pharmaceutical composition of the present invention, it is desirable that the content of preservatives other than the quaternary ammonium salt is small or not contained. Examples of preservatives other than the quaternary ammonium salt include sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, cyclohexidine, boric acid or its salt, and edetic acid or its salt. 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" refers to, for example, an amount that exerts an antiseptic effect alone, and specifically, in a test sample composed of the antiseptic and water, Escherichia coli ATCC 8739 of The bacteria were inoculated so that the concentration of the bacterial liquid was within the range of 10 ⁵ to 10 ⁶ cfu/mL, and mixed uniformly, and the test sample was stored at 20 to 25° C. in the dark and stored for 7 days. 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 measuring the number of viable bacteria (A) was 2.0 or less, preferably. May be 1.5 or less, more preferably 1.2 or less, still more preferably 1.0 or less, particularly preferably 0.8 or less, and most preferably 0.7 or less. More specifically (particularly in the case of boric acid and its salts), preservatives other than quaternary ammonium salts are not contained in an amount of 0.5% (w/v) or more (content is 0.5% (w Less than 0.10% (w/v), more preferably not more than 0.10% (w/v) (content less than 0.10% (w/v)), more preferably 0.05% (w/v). ) Or more, more preferably 0.01% (w/v) or more, even more preferably 0.005% (w/v) or more, even more preferably 0.001%. It is particularly preferable that the content is not less than (w/v), and it is most preferable that the content is not substantially contained. 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. 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. . Particularly, the pharmaceutical composition of the present invention preferably contains no preservative other than edetic acid and salts thereof. 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. The preservative in the present invention refers to a component described as a preservative in the pharmaceutical composition, such as Dorzolamide or a salt thereof in the pharmaceutical composition of the present invention, a component that has an antiseptic effect but is not represented as a preservative. Does not include.

If necessary, additives can be used in the pharmaceutical composition of the present invention, and examples of the additives include surfactants, buffering agents, tonicity agents, stabilizers, antioxidants, and high molecular weight polymers. Coalescence etc. can be added.

The pharmaceutical composition of the present invention can 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.
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- 2-alkylimidazoline, 1-hydroxylethyl-2-alkylimidazoline and the like can be mentioned.
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 pharmaceutical composition of the present invention may contain 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 added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w/v), 0.01 to 5% (w/v) is more preferable, 0.1 to 3% (w/v) is further preferable, and 0.2 to 2% (w/v) is the most preferable.

An isotonicity agent that can be used as a pharmaceutical additive can be appropriately added to the pharmaceutical composition of the present invention. 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 of the present invention can be appropriately blended with a stabilizer that can be used as a pharmaceutical additive. 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 in the case of adding the stabilizer 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 of the present invention can be appropriately blended 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 incorporating the antioxidant into the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the antioxidant and the like, but 0.0001 to 1% (w/v) is preferable. 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 of the present invention may appropriately contain 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, Examples thereof include carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxy vinyl polymer, polyethylene glycol, and the like, and hydroxy ethyl cellulose is preferable. 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 preferred, 0.01-3% (w/v) is more preferred, 0.1-2% (w/v) is even more preferred, and 0.2-1% (w/v) is most preferred.

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

It is particularly preferable that the pharmaceutical composition of the present invention contains hydroxyethyl cellulose as the high molecular weight polymer, mannitol as the tonicity agent, and citric acid or its salt as the buffering agent in combination. As a result, the pharmaceutical composition of the present invention can be rapidly sterilized. In this case, when the respective components are blended in the pharmaceutical composition of the present invention, the content of each component is 0.001 to 5% (w/v) of hydroxyethyl cellulose and 0.01 to 10% of mannitol. (W/v), citric acid or a salt thereof is preferably 0.001 to 10% (w/v), hydroxyethyl cellulose is 0.01 to 3% (w/v), and mannitol is 0.02 to 0.02%. 7% (w/v), more preferably 0.01 to 5% (w/v) of citric acid or a salt thereof, 0.1 to 2% (w/v) of hydroxyethyl cellulose and 0 of mannitol. 1 to 5% (w/v), more preferably 0.1 to 3% (w/v) of citric acid or a salt thereof, and 0.2 to 1% (w/v) of hydroxyethyl cellulose, Most preferably, mannitol is 0.8 to 3% (w/v) and citric acid or its salt is 0.2 to 2% (w/v).

The pH of the pharmaceutical composition of the present invention is preferably 4.0 to 8.0, more preferably 5.0 to 7.5, further preferably 5.5 to 7.3, and 5.5 to 7.0. More preferably, 5.5 to 6.8 is particularly preferable, and 6.0 to 6.8 is most preferable.

The pharmaceutical composition of the present invention is placed in a multi-dose type 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 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 of the present invention is not particularly limited as long as it can be used as a drug, but eye drops are particularly preferable, and the pharmaceutical composition can be manufactured according to a conventional method in the art.

The pharmaceutical composition of the present invention is useful as a therapeutic agent for glaucoma or ocular hypertension.

When administering the pharmaceutical composition of the present invention, the dosage is not particularly limited as long as it is sufficient to achieve the desired drug effect, but it is preferable to apply 1 to 3 drops once, 1 to 3 times a day, It is more preferable to apply 1 to 2 drops once a day and 1 to 2 times a day, and most preferably 1 drop once a day and twice 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 pharmaceutical composition of the present invention is also applied to a product comprising the pharmaceutical composition of the present invention and a multidose type container (containing the pharmaceutical composition), and a method for improving antiseptic efficacy. It

The method for improving preservative efficacy of the present invention contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain boric acid or a salt thereof, or has a boric acid or a salt content of 0.001%. It is less than (w/v), and it is preferable that the method is to improve the antiseptic effect by further containing dorzolamide or a salt thereof in the pharmaceutical composition contained in the multi-dose type container.

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, and even more preferably at most 1.0.

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.

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
Timolol 5mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Formulation example 2 (in a multi-dose container)
Dorzolamide 20mg
Timolol 5mg
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 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 Example 2 and Comparative Examples 1 and 2 were prepared by the same method 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

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

Comparative example 2 (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

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 (also called A. brasiliensis)

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 and 2 and Comparative Example were prepared so that the inoculum bacterial solution was adjusted to 10 ⁵ to 10 ⁶ cfu/mL. Each test inoculum was inoculated into a test sample consisting of the preparations of 1 and 2 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, or 7 days later), 1 mL was sampled from each sample with a micropipette, and the viable cell count 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 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. In some cases, the viable cell count at the time of inspection was reduced to 10% of the inoculated cell count.

表１に示されるように、ドルゾラミド又はその塩及びチモロール又はその塩を含有する実施例１〜２の製剤は、ベンザルコニウム塩化物を含まないにもかかわらず、いずれの菌に対しても防腐効果を示した。これに対し、ドルゾラミド又はその塩を含まない比較例１、チモロール又はその塩を含まない比較例２の製剤は、防腐効果が劣っており、特に、大腸菌に対しては、７日経過後でも、菌数を１オーダー減少させることができなかった。これにより、本発明の医薬組成物は、幅広い菌種に対して優れた防腐効果を示し、マルチドーズ型容器に入れられて、繰り返し容器を開閉して使用されても防腐効果を十分に発揮できることが示唆された。

防腐効力試験（２）
１．被験製剤の調製
実施例１の調製方法と同様の方法にて、実施例３〜６の製剤を調製した。

As shown in Table 1, the preparations of Examples 1 and 2 containing dorzolamide or a salt thereof and timolol or a salt thereof are antiseptic to any fungus, although they do not contain benzalkonium chloride. Showed the effect. On the other hand, the preparations of Comparative Example 1 containing no dorzolamide or a salt thereof and Comparative Example 2 containing no timolol or a salt thereof have poor antiseptic effects, and particularly against E. coli, even after 7 days, The number could not be reduced by one order. Thereby, the pharmaceutical composition of the present invention exhibits an excellent antiseptic effect against a wide range of bacterial species, and can be sufficiently put in a multidose type container and can be sufficiently opened even if the container is repeatedly opened and closed. Was suggested.

Antiseptic test (2)
1. Preparation of Test Preparations The preparations of Examples 3 to 6 were prepared in the same manner as the preparation method of Example 1.

Example 3 (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 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 6.5

Example 5 (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 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
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 3 to 6 containing dorzolamide or a salt thereof and timolol or a salt thereof are preservative against any of the bacteria even though they do not contain benzalkonium chloride. Showed the effect. Thereby, the pharmaceutical composition of the present invention exhibits an excellent antiseptic effect against a wide range of bacterial species, and can be sufficiently put in a multidose type container and can be sufficiently opened even if the container is repeatedly opened and closed. Was suggested.

Antiseptic test (3)
1. Preparation of test preparations The preparations of Comparative Examples 3 and 4 were prepared in the same manner as the preparation method of Example 1.

Comparative Example 3 (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 4 (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 formulations of Comparative Examples 3 and 4, which do not contain dorzolamide or a salt thereof and timolol or a salt thereof, contain edetate disodium dihydrate, which is known to have some preservative effect. However, it was confirmed that it does not exhibit an antiseptic effect against Escherichia coli.

Claims (21)

A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, containing no benzalkonium chloride, containing no preservative other than benzalkonium chloride or containing a predetermined amount,
The predetermined amount is inoculated with a bacterium so that the concentration of ATCC 8739 of Escherichia coli is in the range of 10 ⁵ to 10 ⁶ cfu/mL in a test sample containing the preservative and water. After evenly mixing and storing the test sample in the dark at 20 to 25° C. for 7 days, 1 mL of the test sample was taken with a micropipette and the viable cell count was measured. It is an amount such that the common logarithmic value of the ratio (B/A) of the number of bacteria (B) at the time of inoculation to (A) is 1.0 or less,
The pharmaceutical composition may or may not contain boric acid or a salt thereof. When boric acid or a salt thereof is contained, the content of boric acid or a salt thereof is 0.001% (w/ less than v),
A pharmaceutical composition contained in a multidose container. The pharmaceutical composition according to claim 1, comprising edetic acid or a salt thereof, wherein the content of edetic acid or the salt is 0.0001 to 0.1% (w/v). The pharmaceutical composition according to claim 2, wherein the content of edetic acid or a salt thereof is 0.005 to 0.03% (w/v). The pharmaceutical composition according to claim 2 or 3, wherein the salt of edetic acid is monosodium edetate, disodium edetate, tetrasodium edetate or disodium edetate dihydrate. The pharmaceutical composition according to any one of claims 1 to 4, wherein the dorzolamide or a salt thereof is dorzolamide hydrochloride. The pharmaceutical composition according to any one of claims 1 to 5, wherein timolol or a salt thereof is timolol maleate. The pharmaceutical composition according to any one of claims 1 to 6, wherein the content of dorzolamide or a salt thereof is 0.1-5% (w/v). The pharmaceutical composition according to claim 7, wherein the content of dorzolamide or a salt thereof is 1% (w/v) or 2% (w/v). The pharmaceutical composition according to any one of claims 1 to 8, wherein the content of timolol or its salt is 0.01-2% (w/v). The pharmaceutical composition according to claim 9, wherein the content of timolol or its salt is 0.5% (w/v). The pharmaceutical composition according to any one of claims 1 to 10, which does not contain boric acid or a salt thereof. The pharmaceutical composition according to any one of claims 1 to 11, which further comprises a high molecular weight polymer. 13. The pharmaceutical composition according to claim 12, wherein the high molecular weight polymer comprises hydroxyethyl cellulose. The pharmaceutical composition according to claim 1, further comprising a nonionic tonicity agent. 15. The pharmaceutical composition according to claim 14, wherein the nonionic tonicity agent comprises mannitol. The pharmaceutical composition according to any one of claims 1 to 15, further comprising a buffering agent. The pharmaceutical composition according to claim 16, wherein the buffering agent comprises citric acid or a salt thereof. The pharmaceutical composition according to any one of claims 1 to 17, which has a pH of 4 to 8. The pharmaceutical composition according to claim 18, having a pH of 5.5 to 6.8. The pharmaceutical composition according to any one of claims 1 to 19, which is used for treatment of glaucoma or ocular hypertension. A product comprising the pharmaceutical composition according to any one of claims 1 to 20 and a multidose type container.