TW201309343A - Aqueous composition with improved drug migration properties of hydrophilic drug - Google Patents

Abstract

The present invention provides an aqueous composition which is the aqueous composition containing a hydrophilic drug and wherein it contains a hydrophilic drug and benzalkonium halide, and has the ratio of osmotic pressure of less than 0.5 in order to improve the migration properties of the drug to site of action, express the desired effect of the drug with low dose, and elevate safety of the drug when it being used. It is preferred that the aqueous composition further contains polyalcohol, and benzalkonium halide is benzalkonium chloride.

Description

An aqueous composition for improving drug migration of a hydrophilic drug Background of the invention Field of invention

The present invention relates to an aqueous composition comprising a hydrophilic drug and a benzdimethylammonium halide, and having an osmotic pressure ratio of 0.5 or less. The aqueous composition is one in which the drug migration is improved to the site of action of the drug.

Description of the background art

In order to make the drug an aqueous composition such as eye drops, there are a number of problems to be reviewed, such as the solubility of a drug or the stability of a composition after the adjustment. Among these problems, as a particularly important subject, it is possible to improve the drug migration property to the site of action of the drug so as to exert the desired effect at a low dosage as much as possible.

As an example of the aqueous composition of the drug, for example, in the specification of the US Patent Application Publication No. 2010/0093770 (Patent Document 1), there is described an isotonic eye liquid containing an adenosine derivative and mixed therein. Glycerin; and the adenosine derivative is useful for treating glaucoma. In the specification of U.S. Patent No. 5,710,182 (Patent Document 2), there is described an ophthalmic composition containing a glaucoma therapeutic agent mixed with glycerin and benzalkonium chloride. In the specification of European Patent Application Publication No. 909558 (Patent Document 3), there is described a low osmotic pressure eye agent which contains Anthracene derivatives, mixed with an osmotic pressure adjusting agent; The corneal migration of the anthraquinone derivative has been improved.

Summary of invention

The aqueous composition containing a hydrophilic drug is highly interesting because it improves the migration of the drug to the site of action of the drug, and is related to the efficacy of the drug at a low dosage and the safety of the drug. Question.

Therefore, the inventors of the present invention have directed studies on improving the mobility of a hydrophilic drug to a site of action of a drug. As a result, it was found that an aqueous composition containing the drug as an active ingredient and mixed with a benzdimethylammonium halide; and by making the osmotic pressure of the aqueous composition into a low osmotic pressure, that is, to become an infiltration The present invention can be attained for the purpose of improving the mobility of a hydrophilic drug to a drug-acting site by an aqueous composition having a pressure ratio of 0.5 or less.

The present invention relates to: (1) an aqueous composition comprising a hydrophilic drug and a benzdimethylammonium halide, and having an osmotic pressure ratio of 0.5 or less; (2) an aqueous composition as described in the above (1) And the aqueous composition described in (1) or (2) above, wherein the benzdimethylammonium halide is benzalkonium chloride; (4) as described above (1) Or the aqueous composition described in (2), wherein the partition coefficient CoLogP of the hydrophilic drug is 3 or less; (5) the aqueous composition as described in the above (1) or (2), wherein the hydrophilic drug is used as the hydrophilic drug The partition coefficient CLogP is 3 or less, and the hydrophilic drug is an adenosine derivative or a nucleoside derivative or a salt thereof; (6) The aqueous composition as described in the above (1) or (2), wherein the hydrophilic drug is a compound represented by the following formula (1) or a salt thereof, (7) The aqueous composition according to the above (1) or (2), wherein the concentration of the benzdimethylammonium halide is 0.05 w/v% or less; (8) as described in the above (1) or (2) The aqueous composition, wherein the osmotic pressure ratio is 0.3 or less; (9) The aqueous composition as described in (2) above, wherein the polyol is at least one selected from the group consisting of glycerin, propylene glycol and mannitol. (10) The aqueous composition according to the above (2), wherein the polyol is glycerin; (11) the aqueous composition as described in (2) above, wherein the concentration of the polyol is 5 w/v% or less; The aqueous composition according to the above (1) or (2), wherein the aqueous composition is an injection, an infusion, a nasal spray or an eye drop; (13) the aqueous composition as described in the above (12), wherein the injection is (A) The aqueous composition according to the above (12), wherein the aqueous composition is an eye drop; (15) the aqueous composition as described in the above (14), wherein the eye drop is glaucoma or high eye Eye drops for the treatment of stress.

Further, each of the above configurations (1) to (15) may be arbitrarily selected and combined.

The present invention provides an aqueous composition which is improved as a transition from a hydrophilic drug useful for medicine to a site of action of a drug. By improving the migration of the drug to the site of action of the drug, it is possible to exert a desired effect at a low dose (low concentration). Therefore, the reduction effect due to the side effects of the drug and its decomposition product is expected.

The above and other objects, features, aspects and advantages of the present invention will become apparent from

Description of the preferred embodiment

The hydrophilic drug to be mixed with the aqueous composition of the present invention is not particularly limited as long as it is a hydrophilic drug. Preferably, the CLogP as the partition coefficient is limited to 3 or less, and more preferably: CLogP as a partition coefficient is limited to -5 to 3, and particularly preferably CLogP is limited to -3 to 2. Preferred examples thereof include prostaglandins; beta-blockers such as Atenolol (CLogP: -0.11) and Carteolol (CLogP: 1.29); and brimonidine (Brimonidine). (CLogP: 1.49) and other α2 receptor agonists; bunazosin (CLogP: 2.10) and other α1 receptor blocking drugs; Pilocarpine (CLogP: -0.20), etc. Parasympathetic acting drug; carbonic anhydrase inhibitor such as Brinzolamide (CLogP: 0.33); Rho kinase inhibitor of Y-39983 (CLogP: 1.77); compound represented by the following formula (1) (4-{3-[6-Amino-9-((2R,3R,4S,5S)-5-cyclopropylaminecarbamido-3,4-dihydroxytetrahydrofuran-2-yl)-9H- Indole-2-yl]-2-propynyl}-piperidine-1-carboxylic acid a nucleoside derivative such as ester (CLogP: -0.61); a glaucoma therapeutic or a compound having an ocular hypotensive effect or a salt thereof. As a more preferable specific example, it is described in the pamphlet of International Publication No. 2003/029264, the specification of U.S. Patent No. 7,214,665, the specification of U.S. Patent Application Publication No. 2007/232559, the International Publication No. 2006/015357, and the U.S. Patent. The application publications No. 2006/0040888, U.S. Patent No. 7,605,143, U.S. Patent Application Publication No. 2009/0253647, U.S. Patent No. 5,593,975, U.S. Patent No. 6,387,889, U.S. Patent No. 6,514,949, US Patent Application Publication No. 2006/0100169, International Publication No. 2006/015357, International Publication No. 2006/101920, US Patent Application Publication No. 2005/0182018, International Publication No. 2003/029264 Booklet, International Publication No. 2003/011146, International Publication No. 2005/107463, US Patent Application Publication No. 2004/053881, US Patent Application Publication No. 2005/130930, US Patent No. 5,278,150, U.S. Patent No. 6,403,567, U.S. Patent No. 6,642,210 Adenosine derivatives (including salts, hydrates, etc.) or nucleoside derivatives (including salts, hydrates, etc.) of the prior art, such as the specification of US Pat. No. 6,232,297, the specification of US Pat. No. 6,531,457, and the specification of US Pat. No. 5,395,543. Further, as a further preferred example, a known adenosine derivative or a nucleoside derivative described in the specification of U.S. Patent Application Publication No. 2010/0093770, which is particularly preferred, is represented by the following formula (1). Compound (4-{3-[6-Amino-9-((2R,3R,4S,5S)-5-cyclopropylamine A) Mercapto-3,4-dihydroxytetrahydrofuran-2-yl)-9H-indol-2-yl]-2-propynyl}-piperidine-1-carboxylic acid methyl ester) or a salt thereof.

Further, CLogP is a value obtained by calculating the logarithm of the partition coefficient of the chemical substance 1-octanol/water system, and is described in detail in JP-A-2009-298878. The value calculated by the software CLogP (Ver4.3) manufactured by BioByte Co., Ltd. is shown in the present invention.

Further, the content of the hydrophilic drug is not particularly limited as long as it is sufficient to produce a desired effect, and the content of the hydrophilic drug, the disease or symptom of the subject, the age of the patient, or the body weight may be appropriately adjusted depending on the content of the hydrophilic drug. It is preferably 0.000001 to 10 w/v%, particularly preferably 0.0001 to 1 w/v%.

Further, even if the hydrophilic drug is a compound represented by the above formula (1) or a salt thereof, there is no particular limitation on the amount of the drug to be sufficiently effective. For example, if the compound represented by the above formula (1) or a salt thereof is used for the treatment of glaucoma, the amount thereof is preferably 0.000001 to 10 w/v%, more preferably 0.00001 to 1 w/v%, and particularly preferably 0.0001 to 0.3 w. /v%, further preferably 0.001 to 0.3 w/v%, further preferably 0.003 to 0.1 w/v%, most preferably 0.01 to 0.1 w/v%.

Further, when the hydrophilic drug is in the form of a salt, the salt is generally not particularly limited as long as it is used as a salt of the drug. For example, a salt with an inorganic acid, a salt with an organic acid, a quaternary ammonium salt, a salt with a halogen ion, and a base a metal salt, a salt with an alkaline earth metal, a metal salt, a salt with ammonia, a salt with an organic amine, and the like. 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; and salts with organic acids include acetic acid, oxalic acid, fumaric acid, and horses. Acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptanoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2 -ethane disulfonic acid, 2-hydroxyethanesulfonic acid, lactobionic acid, oleic acid, pamoate, polygalacturonic acid, stearic acid, tannic acid, trifluoro a salt of methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, salicylic acid, etc.; as a quaternary ammonium salt, methane bromide, methane iodide, etc. Examples of the salt with a halide ion include a salt with a bromide ion, a chloride ion, an iodide ion, and the like; and a salt with an alkali metal: a salt with lithium, sodium, potassium or the like; and an alkaline earth metal; The salt may be a salt with calcium or magnesium; and the metal salt may be a salt with iron or zinc; The salt with an organic amine can be exemplified by: triethylene glycol diamine, 2-amine ethanol, 2,2-imine bis(ethanol), 1-deoxy-1-(methylamino)-2-D- Sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, N,N-bis(benzyl)-1,2-ethanediamine, etc. Salt.

The polyol to be mixed with the aqueous composition of the present invention is not particularly limited as long as it has two or more alcoholic hydroxyl groups in its molecule and can be used as a pharmaceutical additive. Specific examples thereof include glycerin, propylene glycol, mannitol, polyethylene glycol, trehalose, sucrose, sorbitol, and xylitol, and preferred examples thereof include glycerin, propylene glycol, and mannitol. Particularly preferred ones are glycerin. Further, two or more kinds of these polyols may be used in combination.

Further, the mixed concentration (mixing amount) of the polyol may be adjusted to the influence of the drug, other additives, and/or osmotic pressure ratio, and the mixing concentration (mixing amount) may be appropriately adjusted, but it is preferably 5 w/v% or less (but It is not 0w/v%), more preferably 3w/v% or less (but not 0w/v%), and particularly preferably 0.01 to 2.5w/v%, particularly preferably 0.05 to 2w/v%.

Further, even when the polyol is glycerin, the mixing concentration (mixing amount) of the drug, other additives, and/or osmotic pressure ratio may be appropriately adjusted, but it is preferably 5 w/v% or less (but not 0w/v%), more preferably 3w/v% or less (but not 0w/v%), particularly preferably 0.01 to 1.5w/v%, particularly preferably 0.05 to 1.1w/v%.

The benzdimethylammonium halide to be mixed with the aqueous composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical additive, and examples thereof include benzalkonium chloride chloride. Benzyldimethylammonium bromide, benzalkonium bromide, benzalkonium iodide, wherein, in particular, from the viewpoint of migration or safety of a hydrophilic drug, benzonitrile chloride is preferred. Ammonium. A specific example of the benzalkonium chloride chloride has a chemical structure represented by [C ₆ H ₅ CH ₂ N(CH ₃ ) ₂ R]Cl, and the R is C ₈ H ₁₇ to C ₁₈ H ₃₇ Or a mixture of such. Preferred is N-benzyl-N,N-dimethyllauryl ammonium chloride of R system C ₁₂ H ₂₅ , N-benzyl-N,N-dimethyl soybean meal of R system C ₁₄ H ₂₉ Alkyl ammonium or R system C ₁₆ H ₃₃ N-benzyl-N-hexadecyldimethylammonium chloride or a mixture of these.

Further, the mixed concentration (mixing amount) of the benzdimethylammonium halide can be appropriately adjusted in terms of the influence on the drug, other additives, and/or the osmotic pressure ratio or the preservative effect thereof, but the mixing concentration (mixing amount) can be appropriately adjusted. Preferably, it is 0.05 w/v% or less (but not 0 w/v%), more preferably 0.001 to 0.03 w/v%, particularly preferably 0.001 to 0.02 w/v%.

The aqueous composition of the present invention has an osmotic pressure ratio of 0.5 or less (but not 0), preferably 0.4 or less (but not 0), more preferably 0.01 to 0.4, still more preferably 0.1 to 0.3, particularly preferably 0.2. ~0.3.

Further, the osmotic pressure ratio in the present invention means the osmotic pressure ratio of the aqueous composition to physiological saline. Also, the value can be measured according to a general method. For example, it can be measured according to the method described in the osmotic pressure measurement method (osmotic concentration measurement method) of the Japanese Pharmacopoeia.

Generally, the osmotic pressure ratio of the aqueous composition is greatly affected by the amount of the drug and the additive contained in the aqueous composition. In the present invention, the osmotic pressure ratio can be adjusted to the above range by appropriately adjusting the mixing amount of each of the substances which affect the osmotic pressure.

The aqueous composition of the present invention can be appropriately mixed with an isotonic agent which is used as a pharmaceutical additive within the range of the above osmotic pressure ratio. Examples of the isotonic agent include an ionic isotonic agent or a nonionic isotonic agent. Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; and examples of the nonionic isotonic agent include glycerin, propylene glycol, mannitol, and sorbitol. The polyol to be mixed with the aqueous composition of the present invention may also function as a nonionic isotonic agent, and it is preferred to use a polyol from the viewpoint of the stability of the hydrophilic drug or the migration property of the hydrophilic drug.

The aqueous composition of the present invention can be mixed and used as a nonionic surfactant as a pharmaceutical additive within the range of the above osmotic pressure ratio. Examples of the nonionic surfactant include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene. Castor oil derivatives, polyoxyethylene polyoxypropylene diol, sucrose fatty acid esters, and the like. Examples of the polyoxyethylene fatty acid ester include polyoxyethylene (40) stearate and the like; and examples of the polyoxyethylene sorbitan fatty acid ester include polysorbate 80 and polysorbate 60. , polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65, etc.; as a polyoxyethylene castor oil derivative, can be enumerated : Polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, polyoxyethylene hardened castor oil 60, polyoxyethylene 5 castor oil, polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, etc.; as polyoxyethylene polyoxypropylene diol, polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (42) Polyoxypropylene (67) diol, polyoxyethylene (54) polyoxypropylene (39) diol, polyoxyethylene (196) polyoxypropylene (67) diol, polyoxyethylene (20) polyoxygen Propylene (20) diol or the like. Preferable examples include polysorbate 80, polyoxyethylene hardened castor oil 60, polyoxyethylene 35 castor oil, and stearic acid polyoxyethylene 40; as a particularly preferable example, polysorbate 80 can be cited. .

The aqueous composition of the present invention can be mixed and used as a buffer for a pharmaceutical additive within the range of the above osmotic pressure ratio. Examples of the buffering agent include phosphoric acid or a salt thereof, boric 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, and ε-aminocaproic acid (ε-aminocaproic acid) ), hydroxymethylaminomethane (Trometamol) and the like. 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 borate include borax, sodium borate, and potassium borate; Examples of the citrate include sodium citrate and disodium citrate; and examples of the acetate include sodium acetate and potassium acetate; and examples of the carbonate include sodium carbonate and sodium hydrogencarbonate; and tartrate. , for example, sodium tartrate, potassium tartrate, and the like.

The mixing concentration (mixing amount) of the buffering agent, the influence of the drug, other additives, and/or the osmotic pressure ratio may be appropriately adjusted, and the mixing concentration (mixing amount) may be appropriately adjusted, preferably 5 w/v% or less, more preferably 3 w. Below /v%, it is preferably 0.01~1w/v%, especially preferably 0.05~0.5.

The aqueous composition of the present invention can be mixed and used as a stabilizer for a pharmaceutical additive within the range of the above osmotic pressure ratio. Examples of the stabilizer include edetic acid and sodium edetate.

The aqueous composition of the present invention can be mixed and used as a pH adjuster for a pharmaceutical additive within the range of the above osmotic pressure ratio. Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, and potassium hydroxide.

The aqueous composition of the present invention has a pH of 4.0 to 8.0, preferably 5.5 to 6.5.

The dosage form of the aqueous composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical. For example, an injection, an infusion, a nasal spray, an ophthalmic aqueous composition (ophthalmic injection, eye drop), and the like can be given. Preferred examples are ophthalmic aqueous compositions (ophthalmic injections, eye drops), and particularly preferred are eye drops.

The aqueous composition of the present invention has sufficient stability as a pharmaceutical. The aqueous composition of the present invention is not particularly limited as to the applicable diseases. For example, eye diseases such as glaucoma or ocular hypertension may be mentioned.

The number of administrations of the aqueous composition of the present invention is not particularly limited as long as it is sufficient to produce a desired effect, and may be based on the type of the hydrophilic drug, the disease or symptom of the subject, the age or weight of the patient. Appropriate choice. For example, when using eye drops for glaucoma treatment, one to several drops (for example, 1 to 3 drops, preferably 1 drop) can be administered 1 to several times a day (for example, 1 to 6). Times).

The preparation method of the aqueous composition of the present invention can be prepared by a widely used method.

The drug migration test, the intraocular pressure drop effect test, the hydrophilicity test of the hydrophilic drug, and the formulation examples of the hydrophilic drug to the aqueous humor are described in Examples 1 to 4 which will be described later.

The drug migration test, the intraocular pressure drop effect test, the hydrophilicity test of the hydrophilic drug, and the formulation examples (Examples 1 to 4) of the hydrophilic drug to the aqueous humor are shown below, but these examples are better understood. The invention is not intended to limit the scope of the invention.

<Example 1: Drug migration test of hydrophilic drug to aqueous humor>

The aqueous composition of the present invention (hereinafter also referred to as "the preparation of the present invention") and the aqueous composition of the comparative object (hereinafter also referred to as "comparative preparation") are used to examine the migration property of the aqueous humor of the hydrophilic drug. Further, as the hydrophilic drug, the compound represented by the above formula (1) is used, that is, (4-{3-[6-amino-9-((2R,3R,4S,5S)-5-cyclopropyl) Aminomethylmercapto-3,4-dihydroxytetrahydrofuran-2-yl)-9H-indol-2-yl]-2-propynyl}-piperidine-1-carboxylic acid methyl ester) (hereinafter also referred to as " This compound").

(1-1) Preparation of the preparation of the present invention and comparative preparation

. Formulation 1 of the present invention (ammonium chloride dimethylammonium chloride (hereinafter also referred to as "BAK") 0.005 w/v% low sheet (osmotic pressure ratio: 0.25))

90 mL of pure water was added to 0.47 g of concentrated glycerin and dissolved. After dissolution, 0.15 g of sodium dihydrogen phosphate and 0.01 g of the present compound were added and dissolved. Further, 5 mL of a 0.1 w/v% BAK solution was added and stirred, and an appropriate amount of sodium hydroxide and hydrochloric acid were added thereto to adjust the pH of the preparation to about 6.0, and then an appropriate amount of pure water was added to make the total amount 100 mL, and 0.01 w/v was contained. % of the present compound of the present invention. The osmotic pressure ratio was measured and the osmotic pressure was measured according to the item of the osmotic pressure measuring method (osmotic concentration measuring method) of the Japanese Pharmacopoeia.

The preparation of the present invention and the comparative preparation shown in Table 1 were prepared in the same manner as in the preparation method of the preparation 1 of the present invention.

(1-2) Test method

The concentration of the present compound in the aqueous humor of the JW strain male white rabbit was measured by LC-MS/MS method in one eye and two hours after the eye was spotted by the LC-MS/MS method. (1 time point 4 eyes).

(injection method and measurement method)

1) 50 μL of each preparation was spotted on the cornea with a microdispenser MICROMAN. After the eye, it will be fixed for about 30 seconds.

2) About 4 mL of pentobarbital preparation (trade name: Somnopentil injection) was injected into the ear vein from the ear vein under the condition that the rabbit was placed under the anesthesia at the designated time.

3) The eyeball is collected after the eyeball is protruded and washed with physiological saline solution.

4) The collected aqueous humor was measured by LC-MS/MS method using 50 μL per eye and pre-treatment, and the average of 4 eyes was presented in the results.

(1-3) Test results

The results (Cmax) measured by the LC-MS/MS method are shown in Table 2.

(1-4) Discussion

As shown in Table 2, in the preparations 1 to 8 of the present invention, the migration of the aqueous humor of the present compound was remarkably improved as compared with the comparative preparations 1 to 3. From the above results, it is understood that the migration property of the hydrophilic drug of the preparation of the present invention to the site of action of the drug is remarkably improved.

<Example 2: Eye pressure drop effect test>

The relationship between the improvement of the migration of the aqueous humor of the hydrophilic drug of the present invention and the actual efficacy, that is, the effect of the reduction in intraocular pressure, is reviewed.

(2-1) Preparation of Formulation 9 of the Invention and Comparative Formulation 4

. Formulation 9 of the invention (BAK 0.005 w/v% low sheet [osmotic pressure ratio: 0.25])

90 mL of pure water was added to 0.47 g of glycerin and dissolved. After the dissolution, 0.15 g of sodium dihydrogen phosphate, 0.05 mL of a 10 w/v% BAK solution, and 0.1 g of the present compound were added and dissolved. Further, an appropriate amount of sodium hydroxide was added to adjust the pH of the preparation to about 6.0, and an appropriate amount of pure water was added thereto so as to have a total amount of 100 mL, which was a preparation 9 of the present invention containing 0.1 w/v% of the present compound.

. Comparative Formulation 4 (BAK0w/v% isotonic)

90 mL of pure water was added to 2.4 g of glycerin and dissolved. After dissolution, 0.15 g of sodium dihydrogen phosphate, 0.1 g of the present compound was added and dissolved. Further, in addition to the addition of an appropriate amount of sodium hydroxide, the pH of the preparation was about 6.0, and an appropriate amount of pure water was added to make the total amount 100 mL, which was a comparative preparation 4 containing 0.1 w/v% of the present compound.

(2-2) Test method

The effect of reducing the intraocular pressure when the preparation of the present invention 9 containing 0.1 w/v% of the present compound or the comparative preparation 4 containing 0.1 w/v% of the present compound was administered in a single eye by 20 μL was examined. Also, Cynomolgus monkey (sex: male, a group of 6 to 8) was used as an experimental animal.

(injection method and measurement method)

1) A drop of 0.4% oxybuprocaine hydrochloride (eye name: Benoxil 0.4% solution) was applied to the eye of an experimental animal to measure the eye for local anesthesia.

2) Immediately before the eyes of each test preparation, the intraocular pressure was measured and used as the initial intraocular pressure.

3) Each test preparation was spotted on one eye of the experimental animal (the contralateral eye was not treated).

4) A drop of 0.4% oxybuprocene hydrochloride eye drops was applied to the intraocular pressure test eye at 2 hours, 4 hours, and 6 hours after each test preparation, and intraocular pressure was measured after local anesthesia. Further, the intraocular pressure was measured three times each, and the average value thereof was presented in the results.

(2-3) Test results

The maximum reduction in intraocular pressure of the eye group of each preparation is shown in Table 3. The maximum decrease in intraocular pressure is expressed as the average of the maximum values of intraocular pressure decreased from the initial intraocular pressure.

In Table 3, the formulation 9 of the present invention represents the average value of the maximum intraocular pressure decrease amplitude of 6 pieces, and the comparative preparation 4 represents the average value of the maximum intraocular pressure decrease amplitude of 8 pieces.

(2-4) Discussion

As is clear from Table 3, the preparation 9 of the present invention containing 0.1 w/v% of the present compound exhibited an excellent intraocular pressure lowering effect with respect to the comparative preparation 4 containing 0.1 w/v% of the present compound. From the above results, it is understood that the preparation of the present invention can obtain a stronger intraocular pressure lowering effect than Comparative Formulation 4.

<Example 3: Stability test of hydrophilic drug> (3-1) Preparation of the preparation of the present invention

. Formulation 10 of the invention (BAK 0.005 w/v% low sheet [osmotic pressure ratio: 0.25])

90 mL of pure water was added to 0.47 g of concentrated glycerin and dissolved. After the dissolution, 0.15 g of sodium dihydrogen phosphate and 0.09 g of the present compound were added and dissolved. Further, 5 mL of a 0.1 w/v% BAK solution was added and stirred, and an appropriate amount of sodium hydroxide and hydrochloric acid were added thereto, and after the pH of the preparation was about 6.0, an appropriate amount of pure water was added and the total amount was 100 mL, and 0.09 w/ was contained. v% of the present compound of the present invention.

(3-2) Test method

After the preparation 10 of the present invention was stored at 5 ° C, 25 ° C, and 40 ° C for 6 months, the content of the compound was quantified by high performance liquid chromatography (HPLC), and the residual ratio was calculated.

(3-3) Test results

The test results are presented in Table 4.

(3-4) Discussion

As is clear from Table 4, the preparation 10 of the present invention containing 0.09 w/v% of the present compound showed stability results after 6 months at 5 ° C, 25 ° C and 40 ° C. From the above results, it is understood that the preparation of the present invention ensures excellent stability.

<prescription example>

The following preparation was obtained according to the production method of Example 1. Further, the compounding amount of each component of the following formulation examples was in a content of 100 mL.

(Formulation Example 1)

(Formulation Example 2)

(Formulation Example 3)

(Formulation Example 4)

(Formulation Example 5)

(Formulation Example 6)

Further, the components of the above-mentioned Formulation Examples 1 to 6, that is, the compounding amount or the mixing ratio of the present compound, the polyol, the benzdimethylammonium halide (benzylammonium chloride), and other additives are It can be appropriately adjusted within the range of the osmotic pressure ratio of the present invention.

While the invention has been described and illustrated in detail, the embodiments of the invention

Claims (15)

An aqueous composition comprising a hydrophilic drug and a benzalkonium halide, and having an osmotic pressure ratio of 0.5 or less. The aqueous composition of claim 1, further comprising a polyhydric alcohol. An aqueous composition according to claim 1 or 2, wherein the benzdimethylammonium halide is benzalkonium chloride. An aqueous composition according to claim 1 or 2, wherein the partition coefficient CLogP of the hydrophilic drug is 3 or less. An aqueous composition according to claim 1 or 2, wherein a partition coefficient CLogP of the hydrophilic drug is 3 or less, and the hydrophilic drug is an adenosine derivative or a nucleoside derivative or a salt thereof. The aqueous composition according to claim 1 or 2, wherein the hydrophilic drug is a compound represented by the following formula (1) or a salt thereof, An aqueous composition according to claim 1 or 2, wherein the concentration of the benzdimethylammonium halide is 0.05 w/v% or less. An aqueous composition according to claim 1 or 2, wherein the osmotic pressure ratio is 0.3 or less. The aqueous composition of claim 2, wherein the polyol is at least one selected from the group consisting of glycerin, propylene glycol, and mannitol. An aqueous composition according to claim 2, wherein the polyol is glycerin. The aqueous composition of claim 2, wherein the concentration of the polyol is 5 w/v% or less. An aqueous composition according to claim 1 or 2, which is an injection, an infusion, a nasal spray or an eye drop. An aqueous composition according to claim 12, wherein the injection is an ophthalmic injection. The aqueous composition of claim 12, which is an eye-dropping agent. For example, the aqueous composition of claim 14 is an eye drop for treating glaucoma or ocular hypertension.