TW201726127A - Pharmaceutical composition containing dorzolamide, polymer and boric acid by adding boric acid or a salt thereof to a pharmaceutical composition of pH 6.0 or lower that contains dorzolamide or a salt thereof and a polymer to inhibit decrease in viscosity over a period of time - Google Patents

Abstract

Decreases over time in the viscosity of a pharmaceutical composition imparted by a polymer are inhibited in a pharmaceutical composition of pH 6.0 or lower containing dorzolamide or a salt thereof. The pharmaceutical composition of the invention inhibits decreases over time in the viscosity of the pharmaceutical composition by causing boric acid or a salt thereof to be contained in a pharmaceutical composition of pH 6.0 or lower that contains dorzolamide or a salt thereof and a polymer.

Description

Medicinal composition containing dorzolamide, polymer and boric acid

The present invention relates to a pharmaceutical composition containing dorzolamide or a salt thereof, a polymer, and boric acid or a salt thereof at pH 6.0 or lower.

The doxoramide which is a carbonic anhydrase inhibitor is used for the treatment of glaucoma or ocular hypertension because of the decrease in intraocular pressure, and the preparation containing dorzolamide is Trusopt (registered trademark). Eye drops are on sale. Further, Patent Document 1 discloses that a composition containing both dorzolamide and timolol has a treatment for high intraocular pressure, and a preparation containing dorzolamide and temolo is Cosopt ( Registered trademark) blended eye drops for sale.

The dorzolamide is a compound which is less stable in an aqueous solution, and in order to ensure stability in an aqueous solution, for example, it is necessary to make the aqueous solution weakly acidic. Therefore, the pH of the above-mentioned Shulu (registered trademark) eye drops is maintained at 5.5 to 5.9, and the pH of the Kangshumu (registered trademark) blending eye drops is maintained at 5.5 to 5.8.

A polymer such as hydroxyethyl cellulose is a component added for the purpose of imparting viscosity or the like to a pharmaceutical composition. The viscosity of the pharmaceutical composition is desirably kept within a certain range because it affects, for example, the retention of the mucosa of the active ingredient. However, the viscosity of the pharmaceutical composition will increase A situation in which the polymer is degraded over time due to light or heat. Further, Patent Document 2 describes that the viscosity of the ophthalmic composition is lowered in the presence of a nonionic surfactant, and it is described that the composition contains vegetable oil such as sesame oil in order to prevent the viscosity from decreasing.

On the other hand, Patent Document 3 describes an aqueous component containing an eye drop containing dorzolamide and temsolo, boric acid, and borax, and is described by using boric acid or a salt thereof without using a preservative. Save effectiveness.

However, in a pharmaceutical composition containing dorzolamide or a salt thereof and a polymer having a pH of 6.0 or less, it is not known that the viscosity of the pharmaceutical composition imparted by the polymer is lowered with time, and the viscosity is suppressed from being suppressed. The literature does not exist.

Prior technical literature Patent literature

Patent Document 1 Japanese Patent Publication Patent No. 2527513

Patent Document 2 Japanese Laid-Open Patent Publication No. 2015-17132

Patent Document 3 International Publication WO2011/013794

Summary of invention

An object of the present invention is to suppress a decrease in viscosity of a pharmaceutical composition imparted by a polymer in a pharmaceutical composition containing dorzolamide or a salt thereof and a polymer having a pH of 6.0 or less.

The present inventors have unexpectedly found that in a pharmaceutical composition containing dorzolamide or a salt thereof and a polymer having a pH of 6.0 or less, the viscosity of the pharmaceutical composition imparted by the polymer is lowered with time, and the cause is found. When the pharmaceutical composition contains boric acid or a salt thereof, the viscosity is lowered, and the present invention has been completed. Specifically, the present invention provides the following.

(1) A pharmaceutical composition comprising dozolamide or a salt thereof, a polymer, and boric acid or a salt thereof, and having a pH of 6.0 or less.

(2) The pharmaceutical composition according to the above (1), wherein the dorzolamide or a salt thereof is dorzolamide hydrochloride.

(3) The pharmaceutical composition according to the above (1) or (2), wherein the content of dorzolamide or a salt thereof is 0.1 to 5% (w/w).

(4) The pharmaceutical composition according to the above (3), wherein the content of dorzolamide or a salt thereof is 0.5% (w/v), 1% (w/v) or 2% (w/v).

(5) The pharmaceutical composition according to any one of the above (1), wherein the polymer is one or more selected from the group consisting of a cellulose polymer and a carboxyvinyl polymer. Polymer.

(6) The pharmaceutical composition according to the above (5), wherein the cellulose-based polymer is selected from the group consisting of hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, and carboxyvinyl polymer. 1 or a plurality of cellulose-based polymers in the group.

(7) The pharmaceutical composition according to any one of (1) to (6), wherein the content of the polymer is 0.001 to 10% (w/w).

(8) The pharmaceutical composition according to the above (7), wherein the content of the polymer is 0.2 to 1% (w/w).

(9) The pharmaceutical composition according to any one of (1) to (8), wherein the content of boric acid or a salt thereof is 0.001 to 10% (w/w).

(10) The pharmaceutical composition according to the above (9), wherein the content of boric acid or a salt thereof is 0.2 to 1.5% (w/w).

The pharmaceutical composition according to any one of the above aspects (1), wherein the pH is from 3.0 to 6.0.

(12) The pharmaceutical composition according to the above (11), wherein the pH is 5.5 to 5.9.

(13) The pharmaceutical composition according to any one of (1) to (12) wherein the viscosity of the pharmaceutical composition is 50 to 700 (mPa.s) at 25 °C.

The pharmaceutical composition according to any one of the above aspects (1), wherein the viscosity of the pharmaceutical composition is 65 to 170 (mPa.s) at 25 °C.

(15) A method for preventing a decrease in the viscosity of a pharmaceutical composition, which comprises containing boric acid or a salt thereof in a pharmaceutical composition containing dorzolamide or a salt thereof and a polymer and having a pH of 6.0 or less.

(16) Use of dorzolamide or a salt thereof, a polymer, and boric acid or a salt thereof for producing a medicine having a pH of 6.0 or less.

Further, each of the configurations (1) to (16) described above may be arbitrarily selected by combining two or more.

According to the present invention, in the pharmaceutical composition containing dorzolamide or a salt thereof and a polymer having a pH of 6.0 or less, the viscosity of the pharmaceutical composition imparted by the polymer can be suppressed from decreasing with time.

Form for implementing the invention

Hereinafter, the present invention will be described in detail.

In the pharmaceutical composition of the present invention, the dorzolamide is a chemical name (4S,6S)-4-ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b] Thioppyran-2-sulfonamide 7,7-dioxide ((4S,6S)-4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran- Compound represented by 2-sulfonamide 7,7-dioxide):

The dorzolamide is not particularly limited as long as it is obtained by a commercially available or conventional production method.

In the pharmaceutical composition of the present invention, dorzolamide may be a salt, and is not particularly limited as long as it is a salt which is acceptable as a medicine. Examples of the salt include a salt formed with an inorganic acid, a salt formed with an organic acid, a quaternary ammonium salt, a salt formed with a halogen ion, a salt formed with an alkali metal, a salt formed with an alkaline earth metal, a metal salt, and A salt formed with an organic amine or the like.

The salt formed with the inorganic acid may, for example, be a salt formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like, and is preferably a salt formed with hydrochloric acid.

Examples of the salt formed with the organic acid include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucohelic acid, and glucose. Aldehydic 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, citric acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalene a salt formed by an acid, sulfinic acid or the like.

The quaternary ammonium salt may, for example, be a salt formed with methyl bromide, methyl iodide or the like.

The salt formed with a halogen ion may, for example, be a salt formed with a chloride ion, a bromide ion, an iodide ion or the like.

The salt formed with an alkali metal may, for example, be a salt formed with lithium, sodium, potassium or the like.

The salt formed with the alkaline earth metal may, for example, be a salt formed with calcium, magnesium or the like.

Examples of the metal salt include salts formed with iron, zinc, and the like.

As the salt formed with the organic amine, there may be mentioned ethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)- 2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, A salt formed by procaine, N,N-bis(phenylmethyl)-1,2-ethanediamine or the like.

In the case of the salt of dorzolamide, a monohydrochloride salt (dorzolamide hydrochloride) is particularly preferred.

In the pharmaceutical composition of the present invention, dorzolamide and the salts may also be in the form of a hydrate or a solvate.

In the pharmaceutical composition of the present invention, the content of dorzolamide or a salt thereof is not particularly limited as long as it is acceptable as a medicine, but is preferably 0.1 to 5% (w/w), more preferably 0.2 to 4%. (w/w), further preferably 0.3 to 3% (w/w), particularly preferably 0.4 to 2.5% (w/w), particularly preferably 0.5% (w/w), 1% (w/w) ), 2% (w/w), 0.5% (w/v), 1% (w/v) or 2% (w/v). Further, in the pharmaceutical composition using the preservative of the present invention, the salt of dorzolamide is contained, and the equivalent value is converted into the content of free dorzolamide. In addition, "% (w/w)" means the mass (g) of the target component (here, dorzolamide) contained in 100 g of the pharmaceutical composition of the present invention, and "% (w/v)" is It means the mass (g) of the target component (here, dorzolamide) contained in 100 mL of the pharmaceutical composition of the present invention. The following is the same unless otherwise specified.

In the pharmaceutical composition of the present invention, the polymer is not particularly limited as long as it is a polymer which can be used as an additive for pharmaceuticals. Examples of the polymer include a cellulose polymer, polyvinyl pyrrolidone, polyvinyl alcohol, a carboxyvinyl polymer, and polyethylene glycol.

Examples of the cellulose-based polymer include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, and hydroxyethyl cellulose. Hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose acetate Succinate), hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, and the like.

In the pharmaceutical composition of the present invention, the polymer is preferably a cellulose polymer or a carboxyvinyl polymer, more preferably a cellulose polymer, and more preferably hydroxyethyl cellulose, hydroxymethyl cellulose, or hydroxy group. Propyl methylcellulose, most preferably hydroxyethyl cellulose.

In the pharmaceutical composition of the present invention, the viscosity (especially the viscosity of hydroxyethyl cellulose) when the polymer is made into a 1% (w/v) aqueous solution is preferably 50 to 100,000 (mPa.s) at 25 ° C. More preferably, it is 100 to 30000 (mPa.s), further preferably 500 to 10,000 (mPa.s), particularly preferably 1000 to 5000 (mPa.s), and most preferably 2000 to 4000 (mPa.s). The viscosity may be a value measured by a method known to those skilled in the art, for example, a value measured according to the sixteenth modified version of the Japanese Pharmacopoeia "Second Method Rotational Viscometer Method", preferably The value measured at 25 ° C according to the Sixteenth Revision Japanese Pharmacopoeia "Second Method Rotational Viscometer Method".

In the pharmaceutical composition of the present invention, the content of the polymer can be appropriately adjusted depending on the type of the polymer, etc., but is preferably 0.001 to 10% (w/w), more preferably 0.01 to 5% (w/w), further. It is preferably 0.05 to 3% (w/w), particularly preferably 0.1 to 2% (w/w), and most preferably 0.2 to 1% (w/w).

In the pharmaceutical composition of the present invention, the boric acid may be a salt of boric acid, and is not particularly limited as long as it is a salt which is acceptable as a medicine. Examples of the salt of boric acid include borax, sodium borate, potassium borate, and the like. Further, in the case where the pharmaceutical composition of the present invention contains a salt of boric acid, the equivalent value is converted into a free boric acid.

In the pharmaceutical composition of the present invention, the content of boric acid or a salt thereof is preferably 0.001 to 10% (w/w), more preferably 0.01 to 5% (w/w), still more preferably 0.05 to 3% (w). /w), particularly preferably 0.1 to 2% (w/w), most preferably 0.2 to 1.5% (w/w).

In the pharmaceutical composition of the present invention, an additive may be used as needed, and as the additive, a surfactant, a buffer, an isotonic agent, a stabilizer, an antioxidant, a preservative, a pH adjuster, or the like may be added.

The pharmaceutical composition of the present invention may be blended with a surfactant which can be used as an additive for pharmaceuticals, for example, a cationic surfactant, an anionic surfactant, or a nonionic surfactant.

Examples of the anionic surfactant include phospholipids and the like, and examples of the phospholipid include lecithin.

Examples of the cationic surfactant include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, mercaptoaminoethyldiethylamine salts, and fatty acid polyamines. a condensate, an alkyl imidazoline, a 1-decylaminoethyl-2-alkylimidazoline, a 1-hydroxyethyl-2-alkylimidazoline or the like.

Examples of the nonionic surfactant include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hardened castor oil, polyoxyethylene castor oil, and polyoxyethylene polyoxypropylene. Glycol, sucrose fatty acid ester, vitamin E TPGS, and the like.

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

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

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

In the case of polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the number of polymerization of ethylene oxide is preferably from 5 to 100, more preferably from 20 to 50, particularly preferably from 30 to 40. The best is 35. Specific examples of the polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyhydrocarbon. Oxygen 40 castor oil and the like.

Examples of the polyoxyethylene polyoxypropylene diol include polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (42) polyoxypropylene (67) diol, and polyoxyethylene (54). Polyoxypropylene (39) diol, polyoxyethylene (196) polyoxypropylene (67) diol, polyoxyethylene (20) polyoxypropylene (20) diol, and the like.

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

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

The content of the surfactant in the case where the surfactant is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc., but is preferably 0.001 to 5% (w/w), more preferably 0.005 to 2% (w/w), further preferably 0.01 to 1% (w/w), most preferably 0.05 to 0.5% (w/w).

The pharmaceutical composition of the present invention can be blended with a buffer which can be used as an additive for pharmaceuticals. Examples of the buffering agent 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, and trishydroxymethylaminomethane ( Trometamol) and so on.

Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; and examples of the citrate include sodium citrate and citric acid. Examples of the acetate include sodium acetate and potassium acetate; and examples of the carbonate include sodium carbonate and sodium hydrogencarbonate; and examples of the tartrate include sodium tartrate and potassium tartrate. Preferred is citric acid or a salt thereof, and particularly preferably sodium citrate.

The content of the buffering agent in the case where the buffering agent is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffering agent, etc., but is preferably 0.001 to 10% (w/w), more preferably 0.01 to 5 % (w/w) is further preferably 0.1 to 3% (w/w), and most preferably 0.2 to 2% (w/w).

In the pharmaceutical composition of the present invention, an isotonic agent which can be used as an additive for a pharmaceutical product can be appropriately blended. In the case of an isotonic agent, An ionic isotonic agent, a nonionic isotonic agent, etc. are mentioned. Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like, and sodium chloride is preferred. The nonionic isotonic agent may, for example, be glycerin, propylene glycol, sorbitol or mannitol, and is preferably mannitol. The content of the isotonic agent in the case where 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, etc., but is preferably 0.01 to 10% (w/w). More preferably, it is 0.02 to 7% (w/w), further preferably 0.1 to 5% (w/w), particularly preferably 0.5 to 4% (w/w), and most preferably 0.8 to 3% (w/ w).

In the pharmaceutical composition of the present invention, a stabilizer which can be used as an additive for a pharmaceutical can be appropriately blended. Examples of the stabilizers include edetic acid, monosodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, sodium citrate, etc. Preferably, it is disodium edetate, and particularly preferably disodium edetate dihydrate. The content of the stabilizer in the case where the stabilizer is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer, and is preferably 0.0001 to 0.5% (w/w), more preferably 0.0005 to 0.3. %(w/w), further preferably 0.001 to 0.1% (w/w), more preferably 0.002 to 0.08% (w/w), still more preferably 0.003 to 0.05% (w/w), especially Preferably, it is 0.005~0.03% (w/w), and the best is 0.007~0.01% (w/w).

In the pharmaceutical composition of the present invention, an antioxidant which can be used as an additive for a pharmaceutical can be appropriately blended. Examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, and the like. Antioxidant in the case of incorporating an antioxidant in the pharmaceutical composition of the present invention The content may be appropriately adjusted depending on the type of the antioxidant, etc., but is preferably 0.0001 to 1% (w/w), more preferably 0.0005 to 0.1% (w/w), still more preferably 0.001 to 0.02% ( w/w), the best is 0.005~0.010% (w/w).

In the pharmaceutical composition of the present invention, a preservative which can be used as an additive for a pharmaceutical product can be appropriately blended. Examples of the preservative include benzalkonium chloride, alkyldimethylbenzylammonium bromide, benzothonium chloride, sorbic acid, and sorbus. Potassium acid, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorobutanol, ethylenediaminetetraacetic acid or a salt thereof. The content of the preservative in the case where the preservative is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the preservative, etc., but is preferably 0.0001 to 3% (w/w), more preferably 0.0005 to 1%. (w/w) is further preferably 0.001 to 0.5% (w/w), and most preferably 0.005 to 0.1% (w/w).

In the pharmaceutical composition of the present invention, a pH adjuster which can be used as an additive for a pharmaceutical product can be appropriately blended. Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, etc., preferably citric acid.

In the pharmaceutical composition of the present invention, the active ingredient of the usable pharmaceutical product may be appropriately blended, but the active ingredient may not be blended. Examples of the active ingredient include an α ₂ receptor agonist such as brimonidine, temmol, befunolol, carteolol, and nipradilol. (nipradiol), betaxolol, levobunolol, metipranolol, etc., beta-blocker, isopropyl unoprostone, pull Prostaglandin derivatives such as latanoprost, travoprost, bimatoprost, and the like.

The pH of the pharmaceutical composition of the present invention is 6.0 or less, preferably 3.0 to 6.0, more preferably 4.0 to 6.0, still more preferably 5.0 to 6.0, particularly preferably 5.5 to 6.0, most preferably 5.5 to 5.9.

The viscosity of the pharmaceutical composition of the present invention is preferably 50 to 700 (mPa.s), more preferably 55 to 500 (mPa.s), still more preferably 60 to 300 (mPa.s), at 25 ° C, The best is 65~200 (mPa.s), and the best is 65~170 (mPa.s). The viscosity is a value measured according to a method known to those skilled in the art, for example, according to the value determined by the Japanese Pharmacopoeia "Second Method Rotational Viscosity Method" of the sixteenth revised version, preferably based on the tenth. Six revised versions of the Japanese Pharmacopoeia "Second Method Rotational Viscometer Method" measured at 25 ° C.

The pharmaceutical composition of the present invention can be placed in a unit dose type container, a multi dose type container, preferably in a multi-dose type container. The unit dose type container refers to a container that is used up at one time, and the multi-dose type container refers to a container that can be opened and closed freely for the purpose of use for a plurality of times. A PFMD (Preservative Free Multi Dose) container having a special structure for preventing an anti-corrosion effect such as a backflow function can also be placed. The material of the container is not particularly limited, and for example, a container made of polyethylene (PE), polypropylene (PP), or polyethylene terephthalate (PET) 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, but it is particularly preferably an eye drop, and can be produced according to a method generally used in the technical field.

The pharmaceutical composition of the present invention is an aqueous composition and is useful, for example, as a prophylactic and/or therapeutic agent for ophthalmology, particularly a prophylactic and/or therapeutic agent for glaucoma or ocular hypertension.

In the case of administering the pharmaceutical composition of the present invention, the dosage is not particularly limited as long as it is sufficient to exert the desired effect, and it is preferably one to three drops once a day, one to five times a day for eye-pointing, and more Good for 1 to 2 drops, 2 to 4 times a day for eye, preferably 1 drop for 1 time, 3 times for 1 day.

The pharmaceutical composition of the present invention is useful as a contact lens (wearer). The type of the contact lens to be used is not particularly limited, and specific examples thereof include a hard contact lens, a soft contact lens, and the like, and may be an oxygen-permeable contact lens. Examples of the soft contact lens include a water-containing soft contact lens, a non-aqueous soft contact lens, a (non-ionic) water-repellent soft contact lens, and the like.

The above detailed description of the pharmaceutical composition of the present invention is also applicable to a method for preventing the viscosity of the pharmaceutical composition of the present invention from being lowered, and a process for producing a drug having a pH of 6.0 or less, or a salt thereof, a polymer, and a boric acid or The use of its salt.

The method for preventing the viscosity of the pharmaceutical composition of the present invention from being lowered is contained in a pharmaceutical composition containing dorzolamide or a salt thereof and a polymer having a pH of 6.0 or less, and further contains boric acid or a salt thereof.

According to the method for preventing the viscosity of the pharmaceutical composition of the present invention from decreasing, the viscosity of the pharmaceutical composition is maintained at 50 to 700 (mPa.s), preferably 55 to 500 (mPa.s) at 25 ° C for a long period of time. More preferably, it is 60 to 300 (mPa.s), further preferably 65 to 200 (mPa.s), and the best is 65~170 (mPa.s). The above long period means at room temperature, preferably 1 to 30 ° C, more preferably 15 to 25 ° C, 6 months or longer, preferably 1 year or longer, more preferably 2 years or longer, further preferably 3 For years or more, the best period is more than 5 years.

[Examples]

The results of the formulation and the viscosity measurement test are shown below, but these are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention.

Formulation example

Representative formulations of the invention are shown below. Further, the blending amount of each component in the following formulation examples was the content in 1 mL of the preparation.

Formulation Example 1

Formulation Example 2

Further, the type, blending amount, and pH of the dorzolamide, the polymer, and the boric acid in the preparation examples 1 and 2 can be appropriately adjusted to obtain a desired composition.

Viscosity test 1. Preparation of the test preparation <Preparation of the preparation of Example 1>

0.57 g of hydroxyethyl cellulose was weighed correctly and put into about 80 g of sterilized pure water. While heating at about 60 ° C, stirring and dissolving, it was allowed to cool at room temperature. Sterilized pure water was added to adjust to a total amount of 100 g. After uniformly stirring, autoclaving (121 ° C, 30 minutes) was carried out to prepare a 0.57% hydroxyethyl cellulose solution. 0.1113 g of dorzolamide hydrochloride was poured into 8.333 g of a 0.57% hydroxyethylcellulose solution and dissolved by stirring. Further, 1N sodium hydroxide was added to adjust to pH 5.65. The preparation of Example 1 was prepared by adding sterile pure water and adjusting it to a total amount of 10 g. The prepared sample was filled in a glass container (Laboran Pack No. 5 product number "9-852-07"), and stored under light shielding at 60 ° C for 8 weeks.

<Preparation of the preparation of Comparative Example 1>

0.1113 g of dorzolamide hydrochloride was added to 8.333 g of a 0.57% hydroxyethylcellulose solution prepared in the same manner as described above, and stirred and dissolved. Then, 0.1 g of boric acid was added and stirred and dissolved. Further, 1N sodium hydroxide was added to adjust to pH 5.65. The preparation of Comparative Example 1 was prepared by adding sterile pure water and adjusting it to a total amount of 10 g. The prepared sample was filled in a glass container (Laboran Pack No. 5 product number "9-852-07"), and stored under light shielding at 60 ° C for 8 weeks.

2. Test method

The viscosity of each preparation immediately after preparation and at 1, 2, 4, and 8 weeks after preparation was measured according to the sixteenth revised Japanese Pharmacopoeia "Second Method Rotational Viscometer Method" using a cone-plate type rotational viscometer. The measurement conditions were as follows.

‧Measuring machine: viscometer DV-II+PRO(BROOKFIELD)

‧Rotation number (RPM): 0.1

‧Measurement temperature: 25 ° C

3. Test results and investigation

The test results are shown in Table 1.

As shown in Table 1, the formulation of Comparative Example 1 containing dorzolamide hydrochloride and hydroxyethylcellulose but not containing boric acid showed a decrease in viscosity over time, but the formulation of Example 1 containing boric acid The viscosity is maintained at 77mPa. In the vicinity of s, the temporal viscosity reduction is suppressed.

Claims (11)

A pharmaceutical composition comprising dozolamide or a salt thereof, a polymer, and boric acid or a salt thereof, and having a pH of 6.0 or less. The pharmaceutical composition according to claim 1, wherein the dorzolamide or a salt thereof is dorzolamide hydrochloride. The pharmaceutical composition according to claim 1 or 2, wherein the content of dorzolamide or a salt thereof is from 0.1 to 5% (w/w). The pharmaceutical composition according to claim 1, wherein the polymer is one or a plurality of polymers selected from the group consisting of a cellulose polymer and a carboxyvinyl polymer. The pharmaceutical composition according to claim 4, wherein the cellulose-based polymer is selected from the group consisting of hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, and carboxyvinyl polymer. Or a plurality of cellulose-based polymers. The pharmaceutical composition according to claim 1, wherein the content of the polymer is 0.001 to 10% (w/w). The pharmaceutical composition according to claim 1, wherein the boric acid or a salt thereof is contained in an amount of from 0.001 to 10% (w/w). The pharmaceutical composition of claim 1, wherein the pH is 3.0 to 6.0. The pharmaceutical composition according to claim 1, wherein the viscosity of the pharmaceutical composition is 50 to 700 (mPa.s) at 25 °C. A method for preventing a decrease in the viscosity of a pharmaceutical composition comprising a boric acid or a salt thereof by a pharmaceutical composition containing dorzolamide or a salt thereof and a polymer and having a pH of 6.0 or less. A use of dorzolamide or a salt thereof, a polymer, and boric acid or a salt thereof for producing a medicine having a pH of 6.0 or less.