JP2017137345A - Pharmaceutical composition containing dorzolamide, polymer, and boric acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To inhibit decreases over time in viscosity of a pharmaceutical composition imparted by a polymer in a pharmaceutical composition of pH 6.0 or lower containing dorzolamide or a salt thereof.SOLUTION: The pharmaceutical composition of the invention inhibits decreases over time in 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.SELECTED DRAWING: None

Description

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

  Dorzolamide, a carbonic anhydrase inhibitor, is useful for the treatment of glaucoma or ocular hypertension because it exhibits an intraocular pressure lowering action, and a preparation containing dorzolamide is marketed as Torsopt (registered trademark) ophthalmic solution. Patent Document 1 describes that a composition containing both dorzolamide and timolol is useful for the treatment of high intraocular pressure, and a preparation containing dorzolamide and timolol is used as a Cosopt (registered trademark) ophthalmic solution. Sold.

  Dorzolamide is a relatively unstable compound in an aqueous solution, and in order to ensure stability in the aqueous solution, for example, the aqueous solution needs to be weakly acidic. Therefore, the pH of the above-mentioned Torsopt (registered trademark) ophthalmic solution is maintained at 5.5 to 5.9, and the pH of the Cosopt (registered trademark) ophthalmic solution 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 the pharmaceutical composition. Since the viscosity of the pharmaceutical composition affects, for example, mucosal retention of the active ingredient, it is desirable to keep it within a certain range. However, the viscosity of the pharmaceutical composition may decrease over time due to degradation of the polymer by light or heat. Patent Document 2 describes that the viscosity of an ophthalmic composition decreases in the presence of a nonionic surfactant, and in order to prevent this decrease in viscosity, vegetable oil such as sesame oil is added to the composition. It is described to contain.

  On the other hand, Patent Document 3 describes an aqueous ophthalmic composition containing dorzolamide and timolol, boric acid and borax, without using a preservative by using boric acid or a salt thereof. It is described that preservation effect is obtained.

  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 decreases with time, and the There is no literature describing suppression of viscosity reduction.

Japanese Patent Gazette Patent No. 2527513 Japanese Patent Laid-Open No. 2015-17132 International Publication WO2011 / 013794

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

  The present inventors have surprisingly found that in a pharmaceutical composition having a pH of 6.0 or less containing dorzolamide or a salt thereof and a polymer, the viscosity of the pharmaceutical composition imparted by the polymer decreases over time, It has been found that by containing boric acid or a salt thereof in the pharmaceutical composition, the decrease in viscosity is suppressed, and the present invention has been completed. Specifically, the present invention provides the following.

  (1) A pharmaceutical composition comprising dorzolamide 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 (1), wherein the dorzolamide or a salt thereof is dorzolamide hydrochloride.

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

  (4) The pharmaceutical composition according to (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 (1) to (4), wherein the polymer is one or more polymers selected from the group consisting of cellulosic polymers and carboxyvinyl polymers. .

  (6) The pharmaceutical composition according to (5), wherein the cellulosic polymer is one or more cellulosic polymers selected from the group consisting of hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, and carboxyvinyl polymer. .

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

  (8) The pharmaceutical composition according to (7), wherein the polymer content 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 (9), wherein the content of boric acid or a salt thereof is 0.2 to 1.5% (w / w).

  (11) The pharmaceutical composition according to any one of (1) to (10), wherein the pH is 3.0 to 6.0.

  (12) The pharmaceutical composition according to (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.

  (14) The pharmaceutical composition according to any one of (1) to (12), wherein the viscosity of the pharmaceutical composition is 65 to 170 (mPa · s) at 25 ° C.

  (15) A method for preventing a decrease in viscosity of a pharmaceutical composition by 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 medicament having a pH of 6.0 or less.

  Note that two or more of the configurations (1) to (16) can be arbitrarily selected and combined.

  According to the present invention, in a pharmaceutical composition having pH 6.0 or less containing dorzolamide or a salt thereof and a polymer, it is possible to suppress a decrease in the viscosity of the pharmaceutical composition imparted by the polymer over time.

  The present invention is described in detail below.

である。ドルゾラミドは、市販または公知の製造方法により得られるものであれば、特に制限されない。 In the pharmaceutical composition of the present invention, dorzolamide has the chemical name (4S, 6S) -4-Ethylamino-6-methyl-5, 6-dihydro-4H-thieno [2,3-b] thiopyran-2-sulfonamide 7, Compounds represented by 7-dioxide:

It is. Dorzolamide is not particularly limited as long as it is commercially available or can be obtained by a known 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 pharmaceutically acceptable salt. 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. Is mentioned.

  Examples of the salt with an inorganic acid include a salt with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like, preferably a salt with hydrochloric acid.

  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, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.

  Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.

  Examples of salts with halogen ions include salts with chloride ions, bromide ions, iodide ions and the like.

  Examples of the salt with an alkali metal include salts with lithium, sodium, potassium and the like.

  Examples of the salt with 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 And 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.

  In the pharmaceutical composition of the present invention, dorzolamide and salts thereof may take the form of hydrates or solvates.

  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 a pharmaceutically acceptable amount, but is preferably 0.1 to 5% (w / w), 0.2 to 4% (w / w) is more preferable, 0.3 to 3% (w / w) is more preferable, 0.4 to 2.5% (w / w) is particularly preferable, and 0.5% (w / w) Particularly preferred are w), 1% (w / w), 2% (w / w), 0.5% (w / v), 1% (w / v) or 2% (w / v). In addition, when the salt of a dorzolamide contains in the pharmaceutical composition in which the preservative of this invention is used, these values are content converted into the free dorzolamide. “% (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)” It means the mass (g) of the target component (here, Dorzolamide) contained in 100 mL of the pharmaceutical composition of the present invention. The same applies hereinafter unless otherwise specified.

  In the pharmaceutical composition of the present invention, the polymer is not particularly limited as long as it is a polymer that can be used as a pharmaceutical additive. Examples of the polymer include cellulosic polymers, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, and the like.

  Examples of cellulosic polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, Examples thereof include carboxymethyl ethyl cellulose and cellulose acetate phthalate.

  In the pharmaceutical composition of the present invention, the polymer is preferably a cellulosic polymer or a carboxyvinyl polymer, more preferably a cellulosic polymer, still more preferably hydroxyethyl cellulose, hydroxymethyl cellulose, or hydroxypropyl methyl cellulose, and most preferably hydroxyethyl cellulose.

  In the pharmaceutical composition of the present invention, the polymer has a viscosity (particularly the viscosity of hydroxyethyl cellulose) in a 1% (w / v) aqueous solution of 50 to 100,000 (mPa · s) at 25 ° C. Those having 100 to 30000 (mPa · s) are more preferred, those having 500 to 10000 (mPa · s) are more preferred, those having 1000 to 5000 (mPa · s) are particularly preferred, and 2000 to The most preferable is 4000 (mPa · s). The viscosity may be a value measured by a method known to those skilled in the art. For example, the viscosity is a value measured by the Japanese Pharmacopoeia “Second Method Rotational Viscometer Method”, preferably the 16th revision. It is a value measured at 25 ° C. according to the 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, but is preferably 0.001 to 10% (w / w), and 0.01 to 5% (w / W) is more preferred, 0.05 to 3% (w / w) is more preferred, 0.1 to 2% (w / w) is particularly preferred, and 0.2 to 1% (w / w) is most preferred preferable.

  In the pharmaceutical composition of the present invention, boric acid may be a boric acid salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt of boric acid include borax, sodium borate, potassium borate and the like. In addition, when the boric acid salt is contained in the pharmaceutical composition of the present invention, these values are contents converted to 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), 0.05 -3% (w / w) is more preferred, 0.1-2% (w / w) is particularly preferred, and 0.2-1.5% (w / w) is most preferred.

  In the pharmaceutical composition of the present invention, additives can be used as necessary. Examples of the additives include surfactants, buffers, isotonic agents, stabilizers, antioxidants, preservatives, pH. A regulator or the like can be added.

  In the pharmaceutical composition of the present invention, a surfactant that can be used as a pharmaceutical additive, for example, a cationic surfactant, an anionic surfactant, or a nonionic surfactant can be blended.

  Examples of anionic surfactants include phospholipids, and examples of phospholipids include lecithin.

  Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl- 2-alkyl imidazoline, 1-hydroxylethyl-2-alkyl imidazoline, etc. are mentioned.

  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, Vitamin E TPGS etc. are mentioned.

  Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate.

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

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

  As 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 preferred and 35 is most preferred. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like.

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

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

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

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

  The pharmaceutical composition of the present invention may contain a buffering agent that can be used as a pharmaceutical additive. 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 citrate includes citric acid. Sodium, disodium citrate and the like can be mentioned. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium bicarbonate. Examples of the tartrate include sodium tartrate, Examples include potassium tartrate. Citric acid or a salt thereof is preferred, and sodium citrate is particularly preferred.

  The content of the buffer when blending the buffer with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer, etc., but is preferably 0.001 to 10% (w / w). 0.01 to 5% (w / w) is more preferable, 0.1 to 3% (w / w) is more preferable, and 0.2 to 2% (w / w) is most preferable.

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

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

  The pharmaceutical composition of the present invention can be appropriately blended with an antioxidant that can be used as a pharmaceutical additive. 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 with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the antioxidant, etc., but is 0.0001 to 1% (w / w). Preferably, 0.0005 to 0.1% (w / w) is more preferable, 0.001 to 0.02% (w / w) is more preferable, and 0.005 to 0.010% (w / w) is more preferable. Most preferred.

  In the pharmaceutical composition of the present invention, a preservative that can be used as a pharmaceutical additive can be appropriately blended. Examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, edetic acid, and salts thereof. It is done. The content of the preservative when blended with the preservative 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), 0.0005 to 1% (w / w) is more preferable, 0.001 to 0.5% (w / w) is more preferable, and 0.005 to 0.1% (w / w) is most preferable.

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

Although the active ingredient of the pharmaceutical which can be used can be mix | blended suitably with the pharmaceutical composition of this invention, it is not necessary to mix | blend an active ingredient. Examples of active ingredients include α ₂ receptor agonists such as brimonidine, timolol, befnolol, carteolol, nipradilol, betaxolol, β receptor blockers such as levobnolol, metipranolol, isopropyl unoprostone, latanoprost, travoprost And prostaglandin derivatives such as bimatoprost.

  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, and 5 0.5 to 6.0 is particularly preferable, and 5.5 to 5.9 is most preferable.

  The viscosity of the pharmaceutical composition of the present invention is preferably 50 to 700 (mPa · s) at 25 ° C, more preferably 55 to 500 (mPa · s), and 60 to 300 (mPa · s). It is more preferable that it is 65-200 (mPa * s), and it is most preferable that it is 65-170 (mPa * s). The viscosity is a value measured by a method known to those skilled in the art, for example, a value measured by the 16th revised Japanese pharmacopoeia “Second Method Rotational Viscometer Method”, preferably the 16th revised Japanese pharmacy. It is a value measured at 25 ° C. according to the “second method rotational viscometer method”.

  The pharmaceutical composition of the present invention can be put in a unit dose type container or a multi-dose type container, and is preferably put in a multi-dose type container. A unit dose type container is a container that can be used once, and a multi-dose type container is a container that can be freely opened and closed for the purpose of multiple use. You may put in the PFMD (Preservative Free Multi Dose) container which has a special structure for exhibiting antiseptic effects, such as a backflow prevention function. There is no restriction | limiting in particular in the raw material of a container, For example, containers made from polyethylene (PE), a product made from polypropylene (PP), a product made from polyethylene terephthalate (PET), etc. 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 an eye drop is particularly preferable and can be produced according to a usual method in the technical field.

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

  When administering the pharmaceutical composition of the present invention, there is no particular limitation on the dosage as long as it is sufficient to achieve the desired drug effect, but it is preferable to instill 1 to 3 drops, 1 to 5 times a day, More preferably, 1 to 2 drops per day, 2 to 4 times per day, most preferably 1 drop per day, 3 times per 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 include hard contact lenses, soft contact lenses, and the like, and oxygen permeable contact lenses may be used. Examples of the soft contact lens include a hydrous soft contact lens, a non-hydrous soft contact lens, and a (nonionic) silicone hydrogel soft contact lens.

  The above detailed description of the pharmaceutical composition of the present invention includes a method for preventing a decrease in viscosity of the pharmaceutical composition of the present invention, and dorzolamide or a salt thereof for producing a pharmaceutical having a pH of 6.0 or less, It also applies to the use of polymers and boric acid or its salts.

  The method for preventing the decrease in viscosity of the pharmaceutical composition of the present invention further comprises containing boric acid or a salt thereof in a pharmaceutical composition having a pH of 6.0 or less containing dorzolamide or a salt thereof and a polymer. .

  According to the method for preventing a decrease in viscosity of the pharmaceutical composition of the present invention, the viscosity of the pharmaceutical composition is 50 to 700 (mPa · s), preferably 55 to 500 (mPa · s) at 25 ° C. for a long time. More preferably, it is kept at 60 to 300 (mPa · s), more preferably 65 to 200 (mPa · s), and most preferably 65 to 170 (mPa · s). The above-mentioned long term is room temperature, preferably 1-30 ° C., more preferably 15-25 ° C., 6 months or longer, preferably 1 year or longer, more preferably 2 years or longer, more preferably 3 years or longer, most preferably Means a period of 5 years or more.

  Although the example of a formulation and the result of a viscosity measurement test are shown below, these are for understanding this invention better and do not limit the scope of the present invention.

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

Formulation Example 1
Dorzolamide 10mg
Hydroxyethylcellulose 5mg
Boric acid 10mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65

Formulation Example 2
Dorzolamide 10mg
Hydroxypropyl methylcellulose 5mg
Boric acid 10mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65

  It should be noted that the desired composition can be obtained by appropriately adjusting the types and blending amounts of dorzolamide, the polymer, and boric acid in Formulation Examples 1 and 2 and the pH.

Viscosity measurement test Preparation of test preparation <Preparation of preparation of Comparative Example 1>
0.57 g of hydroxyethyl cellulose was accurately weighed and poured into about 80 g of sterilized purified water. The mixture was dissolved with stirring while heating at about 60 ° C., and then allowed to cool at room temperature. Sterile purified water was added to adjust the total amount to 100 g. After stirring uniformly, high-pressure steam sterilization (121 ° C., 30 minutes) was performed to obtain a 0.57% hydroxyethyl cellulose solution. 0.1113 g of dorzolamide hydrochloride was added to 8.333 g of a 0.57% hydroxyethyl cellulose solution, and dissolved by stirring. Further, 1N sodium hydroxide was added to adjust the pH to 5.65. The preparation of Comparative Example 1 was prepared by adding sterile purified water to adjust the total amount to 10 g. The prepared sample was filled in a glass container (laboran pack screw tube No. 5, product number “9-852-07”) and stored at 60 ° C. for 8 weeks under light shielding.

<Preparation of the preparation of Example 1>
After adding 0.1113 g of dorzolamide hydrochloride to 8.333 g of a 0.57% hydroxyethylcellulose solution prepared by the same method as described above, stirring and dissolving, 0.1 g of boric acid was added and dissolved by stirring. Further, 1N sodium hydroxide was added to adjust the pH to 5.65. The preparation of Example 1 was prepared by adding sterile purified water to adjust the total amount to 10 g. The prepared sample was filled in a glass container (laboran pack screw tube No. 5, product number “9-852-07”) and stored at 60 ° C. for 8 weeks under light shielding.

2. Test Method According to the 16th revision Japanese Pharmacopoeia “Method 2 Rotational Viscometer Method”, use a cone-plate rotational viscometer to determine the viscosity of each preparation immediately after preparation and 1, 2, 4, 8 weeks after preparation. It was measured. Measurement conditions were as follows.
・ Measurement equipment: VISCOMETER DV-II + PRO (BROOKFIELD)
・ Rotation speed (RPM): 0.1
・ Measurement temperature: 25 ℃

3. Test results and discussion Table 1 shows the test results.

  As shown in Table 1, the formulation of Comparative Example 1 containing dorzolamide hydrochloride and hydroxyethyl cellulose and containing no boric acid decreased in viscosity over time, but the formulation of Example 1 containing boric acid. The viscosity was maintained around 77 mPa · s, and the decrease in viscosity over time was suppressed.

Claims (11)

  A pharmaceutical composition comprising dorzolamide 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 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 0.1 to 5% (w / w).   The pharmaceutical composition according to any one of claims 1 to 3, wherein the polymer is one or more polymers selected from the group consisting of cellulosic polymers and carboxyvinyl polymers.   The pharmaceutical composition according to claim 4, wherein the cellulosic polymer is one or more cellulosic polymers selected from the group consisting of hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, and carboxyvinyl polymer.   The pharmaceutical composition according to any one of claims 1 to 5, wherein the content of the polymer is 0.001 to 10% (w / w).   The pharmaceutical composition according to any one of claims 1 to 6, wherein the content of boric acid or a salt thereof is 0.001 to 10% (w / w).   The pharmaceutical composition according to any one of claims 1 to 7, wherein the pH is 3.0 to 6.0.   The pharmaceutical composition according to any one of claims 1 to 8, wherein the viscosity of the pharmaceutical composition is 50 to 700 (mPa · s) at 25 ° C.   A method for preventing a decrease in viscosity of a pharmaceutical composition by 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.   Use of dorzolamide or a salt thereof, a polymer, and boric acid or a salt thereof for producing a medicament having a pH of 6.0 or less.