JP6877613B2 - Combination of preservative medicines - Google Patents

Description

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

Dorzolamide, a carbonic anhydrase inhibitor, and timolol, a β-receptor blocker, are both used as therapeutic agents for glaucoma or ocular hypertension because they both exhibit an intraocular pressure-lowering effect. Further, it is described in Patent Document 1 that a composition containing both dorzolamide and timolol is useful for treating high intraocular pressure, and a preparation containing both of them is sold as a cosopt (registered trademark) -blended eye drop. Has been done.

By the way, eye drops need to have a certain level of antiseptic effect in order to prevent the growth of fungi and the like due to repeated use. Therefore, the above-mentioned cosopt (registered trademark) -blended eye drops contain benzalkonium as an antiseptic. Contains chloride. On the other hand, considering the effect of benzalkonium chloride on patients, cosopt (registered trademark) -blended eye drops that do not contain benzalkonium chloride are also on the market, but because they do not contain preservatives, A single-use unit dose container or a PFMD (Preservative Free Multi Dose) container is used. That is, it is recognized that eye drops containing both dorzolamide and timolol need to contain benzalkonium chloride or to ensure the antiseptic effect by the structure of the container in order to be used repeatedly.

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 exert an antiseptic effect unless a certain amount of boric acid is contained.

From the viewpoint of convenience, safety, manufacturing cost, etc., a new ophthalmic solution containing dorzolamide and timolol that does not contain benzalkonium chloride and can be used repeatedly without using a container having a special structure is desired. There is.

Japanese Patent No. 2527513 International Publication WO2011 / 013794 Pamphlet

An object of the present invention is to provide a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which can sufficiently exert an antiseptic effect even when the container is repeatedly opened and closed. That is.

Surprisingly, the present inventors may repeatedly open and close the container even though the pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof does not contain benzalkonium chloride. We have found that the antiseptic effect can be sufficiently exerted, and have completed the present invention. Specifically, the present invention provides:

(1) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which does not contain a preservative or contains a predetermined amount.
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 2.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A pharmaceutical composition in a multi-dose container.

(2) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which does not contain a preservative or contains a predetermined amount.
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.5 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A pharmaceutical composition in a multi-dose container.

(3) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which does not contain a preservative or contains a predetermined amount.
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A pharmaceutical composition in a multi-dose 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 so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 2.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A pharmaceutical composition in a multi-dose 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 so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.5 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A pharmaceutical composition in a multi-dose 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 so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A pharmaceutical composition in a multi-dose container.

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

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

(9) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, which does not contain a preservative other than edetic acid and a salt thereof.
The content of the edetic acid or a salt thereof is 0.0001 to 0.1% (w / v).
A pharmaceutical composition in a multi-dose container.

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

(11) The item according to any one of (7) to (10), wherein the salt of edetonic acid is monosodium edetate, disodium edetate, tetrasodium edetate or disodium edetate dihydrate. 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 a salt thereof is timolol maleate.

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

(15) The pharmaceutical composition according to (14), wherein the content of dorzolamide or a salt thereof 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 a salt thereof is 0.01-2% (w / v).

(17) The pharmaceutical composition according to (16), wherein the content of timolol or a salt thereof 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), further containing a nonionic isotonic agent.

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

(23) The pharmaceutical composition according to any one of (1) to (22), further containing a buffer.

(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 the treatment of glaucoma or ocular hypertension.

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

(29) Contains timolol or a salt thereof, without preservatives or in a predetermined amount,
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 2.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A method for improving the antiseptic effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition contained in a multi-dose container.

(30) Contains timolol or a salt thereof, without preservatives or in a predetermined amount,
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.5 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A method for improving the antiseptic effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition contained in a multi-dose container.

(31) Contains timolol or a salt thereof, without preservatives or in a predetermined amount,
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A method for improving the antiseptic effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition contained in a multi-dose container.

(32) Contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain preservatives other than benzalkonium chloride, or contains a predetermined amount.
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 2.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A method for improving the antiseptic effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition contained in a multi-dose container.

(33) Contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain preservatives other than benzalkonium chloride, or contains a predetermined amount.
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.5 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A method for improving the antiseptic effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition contained in a multi-dose container.

(34) Contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain preservatives other than benzalkonium chloride, or contains a predetermined amount.
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.0 or less.
The content of boric acid or a salt thereof is less than 0.001% (w / v),
A method for improving the antiseptic effect by further containing dorzolamide or a salt thereof in a pharmaceutical composition contained in a multi-dose container.

(35) Contains timolol or a salt thereof, does not contain boric acid or a salt thereof, or has a content of boric acid or a salt thereof of less than 0.001% (w / v) and is placed in a multi-dose container. In the pharmaceutical composition,
Furthermore, it is a method for improving the antiseptic effect by containing dorzolamide or a salt thereof.
The pharmaceutical composition before containing the dolzolamide or a salt thereof is prepared so that the bacterial solution concentration of ATCC 8739 of Escherichia Coli is within the range of ^{10 5} to 10 ^{6 cfu / mL.} 7 days after inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25 ° C. in the dark, 1 mL of the pharmaceutical composition was collected with a micropipette and the viable cell count was measured. A method in which 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 inoculation is 2.0 or less.

(36) Contains timolol or a salt thereof and 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) and is placed in a multi-dose container. In the pharmaceutical composition,
Furthermore, it is a method for improving the antiseptic effect by containing dorzolamide or a salt thereof.
The pharmaceutical composition before containing the dolzolamide or a salt thereof is prepared so that the bacterial solution concentration of ATCC 8739 of Escherichia Coli is within the range of ^{10 5} to 10 ^{6 cfu / mL.} 7 days after inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25 ° C. in the dark, 1 mL of the pharmaceutical composition was collected with a micropipette and the viable cell count was measured. A method in which 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 inoculation is 1.5 or less.

(37) Contains timolol or a salt thereof and 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) and is placed in a multi-dose container. In the pharmaceutical composition,
Furthermore, it is a method for improving the antiseptic effect by containing dorzolamide or a salt thereof.
The pharmaceutical composition before containing the dolzolamide or a salt thereof is prepared so that the bacterial solution concentration of ATCC 8739 of Escherichia Coli is within the range of ^{10 5} to 10 ^{6 cfu / mL.} 7 days after inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25 ° C. in the dark, 1 mL of the pharmaceutical composition was collected with a micropipette and the viable cell count was measured. A method in which 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 inoculation is 1.0 or less.

(38) Contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain boric acid or a salt thereof, or has a content of boric acid or a salt thereof of less than 0.001% (w / v). , In the pharmaceutical composition in a multi-dose container,
Furthermore, it is a method for improving the antiseptic effect by containing dorzolamide or a salt thereof.
The pharmaceutical composition before containing the dolzolamide or a salt thereof is prepared so that the bacterial solution concentration of ATCC 8739 of Escherichia Coli is within the range of ^{10 5} to 10 ^{6 cfu / mL.} 7 days after inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25 ° C. in the dark, 1 mL of the pharmaceutical composition was collected with a micropipette and the viable cell count was measured. A method in which 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 inoculation is 2.0 or less.

(39) Contains timolol or a salt thereof, does not contain benzalkonium chloride, does not contain boric acid or a salt thereof, or has a content of boric acid or a salt thereof of less than 0.001% (w / v). , In the pharmaceutical composition in a multi-dose container,
Furthermore, it is a method for improving the antiseptic effect by containing dorzolamide or a salt thereof.
The pharmaceutical composition before containing the dolzolamide or a salt thereof is prepared so that the bacterial solution concentration of ATCC 8739 of Escherichia Coli is within the range of ^{10 5} to 10 ^{6 cfu / mL.} 7 days after inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25 ° C. in the dark, 1 mL of the pharmaceutical composition was collected with a micropipette and the viable cell count was measured. A method in which 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 inoculation 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 has a content of boric acid or a salt thereof of less than 0.001% (w / v). , In the pharmaceutical composition in a multi-dose container,
Furthermore, it is a method for improving the antiseptic effect by containing dorzolamide or a salt thereof.
The pharmaceutical composition before containing the dolzolamide or a salt thereof is prepared so that the bacterial solution concentration of ATCC 8739 of Escherichia Coli is within the range of ^{10 5} to 10 ^{6 cfu / mL.} 7 days after inoculating the bacteria and mixing them uniformly and storing the pharmaceutical composition at 20 to 25 ° C. in the dark, 1 mL of the pharmaceutical composition was collected with a micropipette and the viable cell count was measured. A method in which 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 inoculation is 1.0 or less.

It should be noted that each of the configurations (1) to (40) can be arbitrarily selected and combined in combination of two or more.

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 exert an antiseptic effect even when the container is repeatedly opened and closed. be able to.

Hereinafter, the present invention will be described in detail.
In the pharmaceutical composition of the present invention, the dorzolamide contained is chemical name (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.

In the pharmaceutical composition of the present invention, the timolol contained is chemical name (2S) -1-[(1, 1-Dimethylethyl) amino] -3- (4-morpholin-4-yl-1, 2, 5- thiadiazol-3-yloxy) A compound represented by propan-2-ol.

The dorzolamide and timolol contained in the pharmaceutical composition of the present invention may be salts, and are not particularly limited as long as they are pharmaceutically acceptable salts. 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 the inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, and alanine. , Lactic acid, horse uric acid, 1,2-ethanedisulfonic acid, isetioic 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 toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic 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 the halogen ion include salts with chloride ion, bromide ion, iodide ion and the like.
Examples of the salt with the alkali metal include salts with lithium, sodium, potassium and the like.
Examples of the salt with the 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, and as the salt of timolol, monomaleate (timolol maleate) is particularly preferable.

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

The content of dolzolamide or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is sufficient to exhibit the desired medicinal and antiseptic effects, but is 0.1 to 5% (w / 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 preferably 1% (w / v) or 2% (w / v). When a salt of dorzolamide is contained in the pharmaceutical composition of the present invention, 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. Hereinafter, the same shall apply unless otherwise specified.

The content of timolol or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is sufficient to exert the desired medicinal effect, but is 0.01 to 2% (w / v). 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. Preferably, 0.5% (w / v) is particularly preferable. When a salt of timolol is contained in the pharmaceutical composition of the present invention, these values are the contents converted into free timolol.

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

In the pharmaceutical composition of the present invention, since dorzolamide, which is the active ingredient of the drug, or a salt thereof itself has an antiseptic effect, it may contain no preservative or may be contained in a predetermined amount. Here, the "predetermined amount" refers to, for example, an amount that does not exert an antiseptic effect by itself, and specifically, in a test sample composed of an antiseptic and water, the ATCC 8739 of Eschericia Colli. Inoculate the bacteria so that the concentration of the bacterial solution is ^{within the range of 10 5} to ⁶ cfu / mL, mix them uniformly, and store the test sample at 20 to 25 ° C. in the shade, and then perform the test 7 days later. 1 mL of the sample is collected with a micropipette, and 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 is measured is 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. .. 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 an antiseptic effect by itself, and specifically, in a test sample consisting of benzalconium chloride and water, ATCC of Eschericia Colli. bacterial solution concentration of 8739 were mixed uniformly and inoculated so as to be in the range of ¹⁰ 5 ^~10 6 cfu / mL, at 7 days after Save the test sample at 20-25 ° C. in the dark , 1 mL of the test sample was collected with a micropipette, and 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, the 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 it is most preferable that it is substantially not contained. 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 quaternary ammonium salts 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, it is preferable that the quaternary ammonium salt is contained in a predetermined amount. Here, the "predetermined amount" refers to, for example, an amount that does not exert an antiseptic effect by itself, and specifically, in a test sample composed of the preservative (quaternary ammonium salt other than benzalconium chloride) and water. Inoculate the bacteria so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL, mix them uniformly, and mix the test samples uniformly in 20 to 20 to 20 to After 7 days have passed since the test sample was stored at 25 ° C., 1 mL of the test sample was collected with a micropipette, and the ratio of the number of bacteria (B) at the time of inoculation (B /) to the number of bacteria (A) when the viable cell count was measured. The common logarithmic value 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, and most preferably 0.7 or less. The amount may be. 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 preferably not contained in an amount of 0.005% (w / v) or more, further preferably not contained in an amount of 0.001% (w / v) or more, and not contained in an amount of 0.0005% (w / v) or more. Is more preferable, and 0.0001% (w / v) or more is particularly preferable, and it is most preferable that it is not substantially contained.

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 a salt thereof, edetonic acid or a salt thereof and the like. When the pharmaceutical composition of the present invention contains a preservative other than the quaternary ammonium salt, it is preferable that the preservative is contained in a predetermined amount. Here, the "predetermined amount" refers to, for example, an amount that exerts an antiseptic effect by itself, and specifically, in a test sample composed of the preservative and water, the ATCC 8739 of Eschericia Colli. Inoculate the bacteria so that the concentration of the bacterial solution is ^{within the range of 10 5} to ⁶ cfu / mL, mix them uniformly, and store the test sample at 20 to 25 ° C. under the shade of light, and then perform the test 7 days later. 1 mL of the sample was collected with a micropipette, and 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, preferably 2.0 or less. 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 / v) is preferable, and 0.10% (w / v) or more is not contained (content is less than 0.10% (w / v)), more preferably 0.05% (w / v). ) Or more, more preferably 0.01% (w / v) or more, and even more preferably 0.005% (w / v) or more, 0.001%. It is particularly preferable that it is not contained in an amount of (w / v) or more, and it is most preferable that it is not substantially contained. Examples of boric acid salts include borax, sodium borate, potassium borate and the like. When a salt of boric acid 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 edetic acid or a salt thereof is added to the pharmaceutical composition of the present invention. 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. .005% or more, 0.007% or more, etc.) 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 further preferable, 0.03% (w / v) or less is particularly preferable, and 0.01% (w / v) or less is particularly preferable. w / v) The following is most preferable. Examples of salts of edetonic acid include monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, with disodium edetate being preferred, and disodium edetate dihydrate being particularly preferred. .. In particular, the pharmaceutical composition of the present invention preferably does not contain preservatives 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 the hydrate thereof. The preservative in the present invention refers to a component described as a preservative in the pharmaceutical composition, and a component having an antiseptic effect but not described as a preservative, such as dorzolamide or a salt thereof in the pharmaceutical composition of the present invention. Do not include.

Additives can be used in the pharmaceutical composition of the present invention as needed, and the additives include surfactants, buffers, isotonic agents, stabilizers, antioxidants, and high molecular weight weights. Coalescence etc. can be added.

The pharmaceutical composition of the present invention may contain a surfactant that can be used as a pharmaceutical additive, 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 cationic surfactants are alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolin, 1-acylaminoethyl- Examples thereof include 2-alkyl imidazoline and 1-hydroxyl ethyl-2-alkyl imidazoline.
Examples of nonionic surfactants include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, etc. Examples include vitamin E TPGS.

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 triolate, and polysorbate 65.

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 preferable, and 60 is most preferable. Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60.

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 the 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.

Examples of the polyoxyethylene polyoxypropylene glycol include polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, and 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 stearic acid ester.

Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate.

The pharmaceutical composition of the present invention may contain a buffer that can be used as an additive for pharmaceutical products. 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, and citric acid includes citric acid. Examples include sodium and disodium citrate, examples of acetate include sodium acetate and potassium acetate, examples of carbonate include sodium carbonate and sodium hydrogen carbonate, and examples of tartrate include sodium tartrate and the like. Examples 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), and is 0. 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 most preferable.

The pharmaceutical composition of the present invention may appropriately contain an isotonic agent that can be used as an additive for pharmaceuticals. Examples of the isotonic agent include an ionic isotonic agent and a nonionic isotonic agent. Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like, and sodium chloride is preferable. Examples of the nonionic isotonic agent include glycerin, propylene glycol, sorbitol, mannitol and the like, and mannitol is preferable. The content of the isotonic agent when the isotonic agent is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the isotonic agent, and is 0.01 to 10% (w / w /). v) is preferable, 0.02 to 7% (w / v) is more preferable, 0.1 to 5% (w / v) is further preferable, and 0.5 to 4% (w / v) is particularly preferable. Most preferably 0.8 to 3% (w / v).

Stabilizers that can be used as additives for pharmaceuticals can be appropriately added to the pharmaceutical composition of the present invention. Examples of stabilizers include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, with disodium edetate being preferred, and disodium edetate dihydrate Especially preferable. The content of the stabilizer when the stabilizer is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer and the like, but is 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 preferable. ) Is more preferable, 0.003 to 0.05% (w / v) is more preferable, 0.005 to 0.03% (w / v) is particularly preferable, and 0.007 to 0.01% (w / v) is particularly preferable. v) is most preferable.

Antioxidants that can be used as additives for pharmaceuticals can be appropriately added to the pharmaceutical composition of the present invention. Examples of antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like. The content of the antioxidant when the antioxidant is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant and the like, but is 0.0001 to 1% (w / v). Preferably, 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 pharmaceutical products. Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcelluloseacetate succinate, hydroxypropylmethylcellulosephthalate, Examples thereof include carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol and the like, and hydroxyethyl cellulose is preferable. The content of the high molecular weight polymer when the high molecular weight polymer is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the high molecular weight polymer and the like, but is 0.001 to 5% (w / w /). v) is preferable, 0.01 to 3% (w / v) is more preferable, 0.1 to 2% (w / v) is further preferable, and 0.2 to 1% (w / v) is most preferable.

A pH adjuster that can be used as an additive for a pharmaceutical product can be appropriately added to the pharmaceutical composition of the present invention. Examples of the pH adjuster 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 a combination of hydroxyethyl cellulose as a high molecular weight polymer, mannitol as an isotonic agent, and citric acid or a salt thereof as a buffer. Thereby, the pharmaceutical composition of the present invention can be rapidly sterilized. In this case, when each component is blended in the pharmaceutical composition of the present invention, the content of each component is 0.001 to 5% (w / v) for hydroxyethyl cellulose and 0.01 to 10% for 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 More preferably, it is 7% (w / v), citric acid or a salt thereof is 0.01-5% (w / v), hydroxyethyl cellulose is 0.1 to 2% (w / v), and mannitol is 0. .1 to 5% (w / v), citric acid or a salt thereof is more preferably 0.1 to 3% (w / v), hydroxyethyl cellulose is 0.2 to 1% (w / v), Most preferably, mannitol is 0.8 to 3% (w / v) and citric acid or a salt thereof 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, still more preferably 5.5 to 7.3, and preferably 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 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, the PFMD (Preservative Free Multi Dose) container having a special structure for exerting 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 pharmaceutical product, but eye drops are particularly preferable, and the pharmaceutical composition can be produced according to a usual method in the art.

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

When the pharmaceutical composition of the present invention is administered, the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, but it is preferable to instill 1 to 3 drops at a time, 1 to 3 times a day. It is more preferable to instill 1 to 2 drops at a time, 1 to 2 times a day, and most preferably 1 drop at a time, 2 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 water-containing soft contact lenses, non-water-containing soft contact lenses, and (nonionic) silicone hydrogel soft contact lenses.

The above detailed description of the pharmaceutical composition of the present invention also applies to products comprising the pharmaceutical composition of the present invention and a multi-dose container (containing the pharmaceutical composition), and a method for improving antiseptic efficacy. To.

The method for improving the antiseptic effect 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 content of boric acid or a salt thereof of 0.001%. It is preferably less than (w / v), and it is preferable that the pharmaceutical composition contained in a multidose type container further contains dolzolamide or a salt thereof to improve the antiseptic effect.

In the method for improving the antiseptic efficacy of the present invention, the pharmaceutical composition before containing dolzolamide or a salt thereof has a bacterial solution concentration of ATCC 8739 of Escherichia coli in the pharmaceutical composition of 10 ⁵ to 10 ⁶ Inoculate the bacteria so that they are within the range of cfu / mL, mix them uniformly, store the pharmaceutical composition at 20 to 25 ° C. in the dark, and 7 days later, add 1 mL of the pharmaceutical composition with a micropipette. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when collected and the viable cell count is preferably 2.0 or less, preferably 1.5. It is more preferably 0 or less, and further preferably 1.0 or less.

A method of improving the preservative efficacy of the present invention, a pharmaceutical composition after being contained dorzolamide or a salt thereof described above, bacterial solution concentration of ATCC 8739 10 of the pharmaceutical composition Esukerishia coli (Escherichia Coli) ⁵ Bacteria are inoculated so as to be within the range of 10 to ⁶ cfu / mL, mixed uniformly, and the pharmaceutical composition is stored at 20 to 25 ° C. in the shade of light, and 7 days later, the pharmaceutical composition is micropipette. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when 1 mL was collected and the viable cell count was measured is preferably 2.5 or more. It is more preferably 3.0 or more, further preferably 3.5 or more, and even more preferably 4.0 or more. Alternatively, in the method for improving the antiseptic efficacy of the present invention, the pharmaceutical composition after containing the above-mentioned dorzolamide or a salt thereof is the standard "Category IA" according to the 16th revised Japanese Pharmacopoeia reference information "Preservative efficacy test method". It is preferable to satisfy.

Examples of the drug 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.

Examples of preparation The following is a typical example of preparation of the present invention. In the following formulation example, the blending amount of each component is the content in 1 mL of the formulation.

Pharmaceutical example 1 (in a multi-dose container)
Dorzolamide 10 mg
Timolol 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Pharmaceutical example 2 (in a multi-dose container)
Dorzolamide 20 mg
Timolol 5 mg
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 additives in the above-mentioned preparation examples 1 and 2.

Antiseptic efficacy test (1)
1. 1. Preparation of test product With liquid A, which was obtained by dissolving dolsolamide hydrochloride (22.26 mg), thymorol maleate (6.83 mg), sodium citrate (2.94 mg), and mannitol (16 mg) in water and sterilizing by filtration. Separately, liquid B obtained by dissolving hydroxyethyl cellulose (4.75 mg) in water and performing high-pressure steam sterilization is mixed, and the pH is adjusted to 5.7 with a pH adjuster, and then water is added to make the total volume 1 mL. , The preparation of Example 1 was prepared.

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

The formulations of Example 2 and Comparative Examples 1 and 2 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 6.83 mg
Sodium citrate hydrate 2.94 mg
Mannitol 30 mg
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 6.83 mg
Sodium citrate hydrate 2.94 mg
Mannitol 30 mg
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 30 mg
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:
Escherichia coli ATCC 8739 (also called E. coli)
Pseudomonas aeruginosa ATCC 9027 (also called P. aeruginosa)
Staphylococcus aureus ATCC 6538 (also known as S. aureus)
Yeast and molds:
Candida albicans ATCC 10231 (also known as C. albicans)
Aspergillus brasiliensis ATCC16404 (also called A. brasiliensis)

As bacterial solution concentration in a test sample consisting of the formulation is 10 ⁵ to 10 ⁶ cells / mL (5 strains both), were inoculated with inoculum in the test sample. Specifically, the ^{inoculated bacterial solution was prepared so as to be 10 7} to 10 ⁸ cfu / mL, and the inoculated bacterial solution was adjusted to 10 ⁵ to 10 ⁶ cfu / mL in Examples 1 and 2 and Comparative Examples. Each inoculated bacterial solution was inoculated into a test sample composed of 1 to 2 preparations and mixed uniformly to prepare a sample. These samples were stored at 20 to 25 ° C. under shading, and at each sampling point (6 hours, 24 hours, or 7 days), 1 mL was collected from each sample with a micropipette, and the viable cell count was measured. At each sampling point, the sample solution was sampled by opening the lid and closing the lid.

3. 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 viable cell count was measured. In some cases, it indicates that the viable cell count at the time of inspection was reduced to 10% of the inoculated bacterial count.

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 against any fungus even though they do not contain benzalkonium chloride. It showed an 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 are inferior in antiseptic effect, and in particular, against Escherichia coli, bacteria even after 7 days have passed. The number could not be reduced by one order. As a result, the pharmaceutical composition of the present invention exhibits an excellent antiseptic effect against a wide range of bacterial species, and can sufficiently exert an antiseptic effect even when placed in a multi-dose container and repeatedly opened and closed. Was suggested.

Antiseptic efficacy test (2)
1. 1. Preparation of test preparation 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 6.83 mg
Sodium chloride 9 mg
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 6.83 mg
Sodium chloride 9 mg
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 6.83 mg
Sodium citrate hydrate 2.94 mg
Mannitol 30 mg
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 6.83 mg
Sodium citrate hydrate 2.94 mg
Mannitol 30 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 Antiseptic efficacy test (1) 2. The antiseptic 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. 3. Test Results and Discussion Table 2 shows the test results. The test results in Table 2 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 viable cell count was measured.

As shown in Table 2, the preparations of Examples 3 to 6 containing dorzolamide or a salt thereof and timolol or a salt thereof are antiseptic against any fungus even though they do not contain benzalkonium chloride. It showed an effect. As a result, the pharmaceutical composition of the present invention exhibits an excellent antiseptic effect against a wide range of bacterial species, and can sufficiently exert an antiseptic effect even when placed in a multi-dose container and repeatedly opened and closed. Was suggested.

Antiseptic efficacy test (3)
1. 1. Preparation of test preparation 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 6.83 mg
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 Antiseptic efficacy test (1) 2. The antiseptic efficacy test was carried out by the same method as the test method. However, the sampling point was set to 7 days later.

3. 3. Test Results and Discussion Table 3 shows the test results. The test results in Table 3 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 viable cell count was measured.

As shown in Table 3, the preparations of Comparative Examples 3 and 4 containing dorzolamide or a salt thereof and timolol or a salt thereof contain disodium edetate dihydrate which is known to have some antiseptic effect. However, it was confirmed that it does not show any antiseptic effect against Escherichia coli.

Claims (21)

A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, comprising a predetermined amount of a preservative.
The predetermined amount is inoculated so that the bacterial solution concentration of ATCC 8739 of Escherichia Colli is ^{within the range of 10 5} to 10 ⁶ cfu / mL in the test sample consisting of the preservative and water. After 7 days have passed since the test sample was stored at 20 to 25 ° C. under shading, 1 mL of the test sample was collected with a micropipette and the viable cell count was measured. The ratio (B / A) of the number of bacteria (B) at the time of inoculation to (A) is an amount such that the common logarithmic value is 1.0 or less.
The pharmaceutical composition may contain boric acid or a salt thereof, and when boric acid or a salt thereof is contained, the content of boric acid or a salt thereof is less than 0.001% (w / v).
A pharmaceutical composition in a multi-dose container. The pharmaceutical composition according to claim 1, wherein the preservative is benzalkonium chloride or edetic acid or a salt thereof. The pharmaceutical composition according to claim 2, wherein the content of edetic acid or a salt thereof 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 any one of claims 2 to 4, wherein the salt of edetonic acid is monosodium edetate, disodium edetate, tetrasodium edetate or disodium edetate dihydrate. The pharmaceutical composition according to any one of claims 1 to 5, wherein dorzolamide or a salt thereof is dorzolamide hydrochloride. The pharmaceutical composition according to any one of claims 1 to 6, wherein timolol or a salt thereof is timolol maleate. The pharmaceutical composition according to any one of claims 1 to 7, wherein the content of dorzolamide or a salt thereof is 0.1-5% (w / v). The pharmaceutical composition according to claim 8, 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 9, wherein the content of timolol or a salt thereof is 0.01-2% (w / v). The pharmaceutical composition according to claim 10, wherein the content of timolol or a salt thereof is 0.5% (w / v). The pharmaceutical composition according to any one of claims 1 to 11, further containing a high molecular weight polymer. The pharmaceutical composition according to claim 12, wherein the high molecular weight polymer contains hydroxyethyl cellulose. The pharmaceutical composition according to any one of claims 1 to 13, further containing a nonionic isotonic agent. The pharmaceutical composition according to claim 14, wherein the nonionic isotonic agent contains mannitol. The pharmaceutical composition according to any one of claims 1 to 15, further comprising a buffer. The pharmaceutical composition according to claim 16, wherein the buffering agent contains citric acid or a salt thereof. The pharmaceutical composition according to any one of claims 1 to 17, wherein the pH is 4 to 8. The pharmaceutical composition according to claim 18, which has a pH of 5.5 to 6.8. The pharmaceutical composition according to any one of claims 1 to 19, which is used for the treatment of glaucoma or ocular hypertension. A product comprising the pharmaceutical composition according to any one of claims 1 to 20 and a multi-dose type container.