JP2015024990A - Aqueous pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a clear aqueous pharmaceutical composition that comprises a poorly water-soluble angiotensin II receptor antagonist as an active ingredient, and a method of producing the same.SOLUTION: An aqueous pharmaceutical composition of an angiotensin II receptor antagonist is obtained by the coexistence of (A) an angiotensin II receptor antagonist, and (B) an amine and (C) a water-soluble polymer.

Description

The present invention provides a clear aqueous pharmaceutical composition containing a poorly water-soluble angiotensin II receptor antagonist as an active ingredient, and a method for producing the same.

Examples of angiotensin II receptor antagonists include candesartan cilexetil, candesartan, valsartan, olmesartan, olmesartan medoxomil, telmisartan, irbesartan, azilsartan, azilsartan medoxomil, and losartan potassium. Known as a drop-in medicine.

Many of the angiotensin II receptor antagonists currently on the market are poorly water-soluble. For example, the solubility of candesartan cilexetil, valsartan, olmesartan medoxomil, telmisartan, irbesartan, azilsartan, azilsartan medoxomil in water is 0.01% (0.01 g / 100 mL) or less, and is hardly soluble in water.

The angiotensin II receptor antagonist is formulated as a solid oral drug. However, if liquid pharmaceuticals can be produced stably by solubilization, the administration route can be expanded by multiple dosage forms such as injections, eye drops, nasal drops, ear drops, etc., and can be administered in various ways It becomes.

As an application example of a solution of a poorly water-soluble angiotensin II receptor antagonist, Japanese Patent Application Laid-Open No. 8-67674 discloses an experimental result that the intraocular pressure was reduced by instilling a white rabbit with candesartan cilexetil suspension. It is disclosed. In addition, Patent No. 4276768 reports that an angiotensin II receptor antagonist can be advantageously used for the prevention, treatment or suppression of progression of simple retinopathy or preproliferative retinopathy, among which suspended ophthalmic solution The formulation example of is disclosed.

In terms of eye drops, the difference in practicality and feeling of use between suspension formulations and clear aqueous formulations is very large. The use of overturning and nebulization after instillation, which is required every time a suspension formulation is used, is a factor that significantly reduces patient adherence, and a clear aqueous formulation is preferred for patients. .

In addition, in the production method, the suspension ophthalmic solution requires a complicated sterilization process and cannot be as simple as filter sterilization like aqueous ophthalmic solution. Therefore, not only preparation takes time, but also the production equipment and production cost become expensive, and it becomes difficult to ensure the sterility of the eye drop.

There is a need for a technique for solubilizing a poorly water-soluble angiotensin II receptor antagonist as a pharmaceutical product into a clear aqueous pharmaceutical composition.

JP-A-8-67674 Japanese Patent No. 4276768

The problem to be solved by the present invention is to provide a clear aqueous pharmaceutical composition in which an angiotensin II receptor antagonist that is poorly water-soluble is solubilized, and an angiotensin II receptor antagonist is dissolved, and a method for producing the same. .

As a result of diligent research aimed at solving the above-mentioned problems, the present inventors combined (B) amine and (C) a water-soluble polymer to form a poorly water-soluble angiotensin II receptor antagonist in water. We found a solubilization technique. The present invention has been completed based on such findings.

The present invention provides pharmaceutical compositions and production methods thereof shown in the following [1] to [12].
[1] The aqueous pharmaceutical composition comprising (A) an angiotensin II receptor antagonist, (B) an amine and (C) a water-soluble polymer [2] and (D) further comprising a surfactant. Aqueous pharmaceutical composition [3] Furthermore, (E) the aqueous pharmaceutical composition [4] according to [1] or [2] containing an isotonic agent, (A) an angiotensin II receptor antagonist is candesartan cilexetil, [1] to [3] including at least one selected from the group consisting of candesartan, valsartan, losartan potassium, olmesartan, olmesartan medoxomil, telmisartan, irbesartan, azilsartan, azilsartan medoxomil, and pharmacologically acceptable salts or derivatives thereof The aqueous pharmaceutical composition [5] according to any one of (5) (A) an angiotensin II receptor antagonist Aqueous pharmaceutical composition [6] according to any one of [1] to [4], which is ndesartan cilexetil [6] (B) amine is meglumine, monoethanolamine, 2-amino-2-methyl-1 The aqueous pharmaceutical composition according to any one of [1] to [5], comprising at least one selected from the group consisting of -propanol, trometamol, diethanolamine, triethanolamine, glucosamine, triethylamine, lysine, arginine and histidine [7] (C) The aqueous pharmaceutical composition according to any one of [1] to [6], wherein the water-soluble polymer is polyvinylpyrrolidone [8] (D) The surfactant is polyoxyethylene hydrogenated castor oil , Polysorbate, polyoxyl stearate, tyloxapol, polyoxyethylene polyoxypropylene glycol, polyoxyethylene The aqueous pharmaceutical composition [9] (E) isotonic agent according to any one of [1] to [7], comprising at least one selected from the group consisting of castor oil and benzalkonium chloride, [10] The aqueous pharmaceutical composition [10] according to any one of [1] to [8], comprising at least one selected from the group consisting of glycerin, propylene glycol, mannitol, glucose, sorbitol, xylitol, sodium chloride and potassium chloride. ] (A) A method for producing an aqueous pharmaceutical composition comprising a step of mixing an angiotensin II receptor antagonist, (B) an amine, and (C) a water-soluble polymer [11] and (D) a step of mixing a surfactant. A method [12] for producing an aqueous pharmaceutical composition according to [10], further comprising (E) a step of mixing an isotonic agent, and an aqueous pharmaceutical composition according to [10] or [11] Manufacturing method

The aqueous pharmaceutical composition of the present invention can be used mainly as a liquid agent for ophthalmic compositions, nasal compositions, eardrop compositions, injectable compositions, and the like.

Since the aqueous pharmaceutical composition of the present invention does not include a complicated manufacturing process at the time of preparation, as compared with the case of a suspension preparation, it is expected that sterility is easily ensured.

In addition, the aqueous preparation for eye drops of the present invention is expected to reduce overturning stirring and fogging during instillation that occurs each time use is a burden on the patient.

Examples of the (A) angiotensin II receptor antagonist used in the present invention include candesartan cilexetil, candesartan, valsartan, losartan potassium, olmesartan, olmesartan medoxomil, telmisartan, irbesartan, azilsartan, azilsartan medoxomil, and pharmacologically acceptable thereof. Preferred salts are candesartan cilexetil, candesartan, valsartan, olmesartan medoxomil, telmisartan, irbesartan, and azilsartan, and particularly preferred is candesartan cilexetil. Each drug concentration is not particularly limited as long as the therapeutic effect by the drug is obtained, but is usually 0.001 to 10 w / v%, preferably 0.01 to 5 w / v%, more preferably 0.05. ~ 3 w / v%.

In addition to (A) the angiotensin II receptor antagonist, the following may be included as a drug further blended in the composition of the present invention. Non-selective adrenergic drugs such as dipivefrine hydrochloride and epinephrine; α2-receptor selective adrenergic drugs such as brimonidine and apraclonidine hydrochloride; parasympathomimetic drugs such as pilocarpine hydrochloride, distigmine bromide and neostigmine methyl sulfate; timolol Β-blockers such as maleate, carteolol hydrochloride, nipradilol, betaxolol hydrochloride, levobunolol hydrochloride; prostaglandin derivatives such as isopropyl unoprostone, bimatoprost, latanoprost, travoprost, tafluprost; dorzolamide hydrochloride, brinzolamide, etc. Carbonic anhydrase inhibitors; Rho kinase inhibitors such as fasudil; acitazanolast hydrate, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate , Tranilast, ibudilast, peromilast potassium, olopatadine hydrochloride and other antiallergic agents; synthesis of betamethasone sodium phosphate, fluorometholone, dexamethasone, hydrocortisone, triamcinolone, triamcinolone acetonide, triamcinolone hexanide, difluprednate, prednisolone acetate Corticosteroids; non-steroidal anti-inflammatory drugs such as indomethacin, pranoprofen, loxoprofen sodium, diclofenac sodium, bromfenac sodium hydrate, nepafenac, meloxicam, lornoxicam; immunosuppressive drugs such as cyclosporine and tacrolimus; Anti-inflammatory drugs such as sodium azulene sulfonate, dipotassium glycyrrhizinate, lysozyme hydrochloride; carbenicillin sodium , Cefmenoxime hydrochloride, chloramphenicol, sodium colistin methanesulfonate, gentamicin sulfate, erythromycin lactobionate, azithromycin, tobramycin, kanamycin, fradiomycin sulfate, micronomycin hydrochloride, ciprofloxacin hydrochloride, lomefloxacin Antibacterial agents such as hydrochloride, ofloxacin, levofloxacin hydrate, norfloxacin, pazufloxacin tosylate, tosufloxacin tosylate, gatifloxacin, moxifloxacin hydrochloride, besifloxacin hydrochloride, tetracycline, doxycycline, minocycline; pimalysin, fluconazole , Antifungals such as miconazole nitrate, amphotericin B; acyclovir, ganciclovir, cidofovir, sorib Antiviral drugs such as amino acids, idoxuridine, adenine arabinoside, trifluorothymidine; corneal disorders such as aminoethylsulfonic acid, amino acids, sodium chondroitin sulfate, sodium hyaluronate, diquafosol sodium, rebamipide, or dry eye treatment Medicines: Vitamins such as cyanocobalamin, flavin adenine dinucleotide sodium, ascorbic acid, thiamine, niacin, folic acid, pyridoxal, pantothenic acid, biotin, retinol palmitate, tocopherol, phylloquinone, menaquinone; lidocaine hydrochloride, oxybuprocaine hydrochloride, etc. Local anesthetics: amlodipine besylate, benidipine hydrochloride, diltiazem hydrochloride, nifedipine, verapamil hydrochloride, azelnidipine, cilnidipine, manidipine salt Calcium antagonists such as acid salt, efonidipine hydrochloride, nitrendipine; polyphenols such as anthocyanin, isoflavone, resveratrol, ellagic acid, chlorogenic acid; carotenoids such as β-carotene, astaxanthin, zeaxanthin, lutein; sesamin, edaravone, SOD and its derivatives, antioxidants such as glutathione and cysteine; endothelin receptor antagonists such as bosentan hydrate and ambrisentan; adenosine A3 receptor agonists such as B-MECA; memantine hydrochloride, amantadine hydrochloride, ketamine NMDA receptor antagonists such as hydrochloride, dextromethorphan, and methadone; cannabinoid receptor agonists such as WIN55212-2; ramelteon, 5-methoxycarbonylamino-N-acetyltryptami Melatonin receptor agonists such as agomelatine; can be exemplified stand spiron citric acid, and the like serotonin receptor agonists such as AL-34662.
The blending amount of these drugs is not particularly limited as long as the effect is obtained, but is usually 0.001 to 10 w / v%.

The amine (B) used in the present invention is not particularly limited as long as the effects of the present invention are obtained, but monoethanolamine, diethanolamine, triethanolamine, meglumine, glucosamine, 2-amino-2-methyl-1- Propanol, trometamol, triethylamine, lysine, arginine, histidine, etc. are preferred, particularly preferred is meglumine, monoethanolamine, 2-amino-2-methyl-1-propanol, trometamol, most preferred meglumine, monoethanolamine , Trometamol.
These amines may be used alone or in combination of two or more.

In the present invention, the weight ratio of (A) angiotensin II receptor antagonist to (B) amine is usually 1: 0.02 to 1: 700, preferably 1: 0.2 to 1:14, more preferably It is in the range of 1: 0.2 to 1: 8, most preferably 1: 0.2 to 1: 3.

The water-soluble polymer (C) used in the present invention is not particularly limited as long as the effects of the present invention can be obtained except for polysaccharides, but polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are preferable, Particularly preferred is polyvinylpyrrolidone. These polymers may be used alone or in combination of two or more.

The weight ratio of (A) angiotensin II receptor antagonist to (C) water-soluble polymer in the present invention is usually 1: 0.001 to 1: 500, preferably 1: 0, as (A) :( C). 0.001 to 1:14, more preferably 1: 0.005 to 1: 8, and most preferably 1: 0.01 to 1: 6.

Although there is no restriction | limiting in particular in the viscosity average molecular weight of polyvinylpyrrolidone used for this invention, 1,000-1,000,000 are preferable and 10,000-700,000 are especially preferable. It is also possible to adjust the viscosity average molecular weight by mixing two or more types of polyvinylpyrrolidone having different viscosity average molecular weights.
Although there is no restriction | limiting in particular in the average degree of polymerization of the polyvinyl alcohol used for this invention, 700-4,500 are preferable and 900-3,500 are especially preferable. It is also possible to adjust the average degree of polymerization by mixing two or more types of polyvinyl alcohol having different viscosity average molecular weights.
Although there is no restriction | limiting in particular in the weight average molecular weight of the polyethyleneglycol used for this invention, 300-50,000 are preferable and 1,000-20,000 are especially preferable. It is also possible to adjust the weight average molecular weight by mixing two or more kinds of polyethylene glycols having different viscosity average molecular weights.

The surfactant (D) used in the present invention is not particularly limited as long as the effects of the present invention can be obtained, but preferably polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, tyloxapol. , Polyoxyethylene polyoxypropylene glycol, benzalkonium chloride, particularly preferably polysorbate 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil 60, polyoxyl 40 stearate, tyloxapol, polyoxyethylene polyoxypropylene Examples include glycols and benzalkonium chlorides, and most preferable examples include nonionic surfactants such as polysorbate 80 and polyoxyethylene hydrogenated castor oil 60. These surfactants may be used alone or in combination of two or more.
(A) An angiotensin II receptor antagonist, (B) an amine, and (C) a water-soluble polymer, and (D) a surfactant is also allowed to coexist, whereby (A) an angiotensin II receptor antagonist is solubilized. The time required can be shortened.

In the present invention, the weight ratio of (A) angiotensin II receptor antagonist to (D) surfactant is usually 1: 0.0001 to 1: 500, preferably 1: 0. 0005 to 1: 6, more preferably 1: 0.001 to 1: 4, and most preferably 1: 0.001 to 1: 1.

The (E) isotonic agent used in the present invention is not particularly limited as long as the effects of the present invention are obtained, but preferably sugars such as glucose, sugar alcohols such as mannitol, sorbitol, xylitol, propylene glycol, glycerin. Sodium chloride and potassium chloride, particularly preferably glycerin, propylene glycol, mannitol and the like, most preferably glycerin, propylene glycol and the like. These tonicity agents may be used alone or in combination of two or more.
(A) An angiotensin II receptor antagonist, (B) amine and (C) a water-soluble polymer and (E) an isotonic agent coexist to make the pharmaceutical composition an osmotic pressure ratio suitable as a pharmaceutical product. Can be adjusted.

The pH of the aqueous pharmaceutical composition in the present invention is 4.5 to 9.0, preferably 5.0 to 9.0, more preferably 5.5 to 8.5, and most preferably 6.0 to 8.0.
In order to adjust the pH of the aqueous pharmaceutical composition of the present invention, various pH adjusters that are usually added are used. Examples of the acids include ascorbic acid, hydrochloric acid, glucuronic acid, gluconic acid, acetic acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, sulfuric acid, citric acid, malic acid, tartaric acid and the like. Examples of the base include borax, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide and the like. Examples of other pH adjusters include amino acids such as glycine, histidine, and epsilon aminocaproic acid. Among these, hydrochloric acid, phosphoric acid, and sodium dihydrogen phosphate are preferable, and sodium dihydrogen phosphate is particularly preferable.

In preparing the aqueous pharmaceutical composition of the present invention, pharmaceutically acceptable solubilizers, stabilizers, preservatives and the like may be added as necessary to the extent that the effects of the present invention are not impaired. It can be added to a pharmaceutical composition.
Examples of the stabilizer include polysaccharides such as methyl cellulose, hypromellose, hydroxyethyl cellulose, sodium hyaluronate, sodium carboxymethyl cellulose, and among them, methyl cellulose, sodium hyaluronate, and sodium carboxymethyl cellulose are preferable.
Preservatives include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, polydronium chloride and other inverse soaps, parahydroxybenzoic acid methyl, parahydroxybenzoic acid propyl, parahydroxybenzoic acid butyl and other parabens, chloro Alcohols such as butanol, phenylethyl alcohol and benzyl alcohol, organic acids such as sodium dehydroacetate, sorbic acid and potassium sorbate, and salts thereof can be used.
Other additives include stabilizers such as ethylenediaminetetraacetic acid and pharmaceutically acceptable salts thereof, tocopherol and derivatives thereof, sodium citrate, taurine, epsilon aminocaproic acid, sodium sulfite and the like.

Viscosity of methylcellulose, hypromellose and hydroxyethylcellulose used in preparing the aqueous pharmaceutical composition of the present invention in a 2 w / v% aqueous solution varies depending on the type and degree of substitution, but is not particularly limited. 1 to 150,000 is preferable, and 3 to 12,000 is particularly preferable. Viscosity can be obtained by mixing two or more types of methyl cellulose having different viscosity average molecular weights, mixing two or more types of hypromellose having different viscosity average molecular weights, or mixing two or more types of hydroxyethyl cellulose. It is also possible to adjust.
The average molecular weight of sodium hyaluronate used in preparing the aqueous pharmaceutical composition of the present invention is not particularly limited, but is preferably 10,000 to 2,000,000, particularly preferably 500,000 to 1,200,000. . It is also possible to adjust the average molecular weight by mixing two or more kinds of sodium hyaluronate.
Although there is no restriction | limiting in particular in the average molecular weight of the carboxymethylcellulose sodium used in preparing the aqueous | water-based pharmaceutical composition of this invention, 50,000-1,000,000 are preferable and 90,000-700,000 are especially preferable. It is also possible to adjust the weight average molecular weight by mixing two or more sodium carboxymethyl celluloses.

The osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention is not particularly limited as long as the effect of the present invention is obtained, but is usually 0.5 to 2.0, preferably 0.7 to 1.8, more preferably. Is 0.8 to 1.6, most preferably 0.9 to 1.5.

The weight ratio of (A) angiotensin II receptor antagonist, (B) amine, and (C) water-soluble polymer, which is a constituent element of the invention, is usually 1: 0 as (A) :( B) :( C). .02: 0.001 to 1: 700: 500, preferably 1: 0.2: 0.001 to 1:14:14, more preferably 1: 0.2: 0.005 to 1: 8: 8, most preferably 1: 0.2: 0.01 to 1: 3: 6.
The weight ratio of (A) angiotensin II receptor antagonist, (B) amine, (C) water-soluble polymer, and (D) surfactant is (A) :( B) :( C) :( D ), Usually 1: 0.02: 0.001: 0.0001 to 1: 700: 500: 500, preferably 1: 0.2: 0.001: 0.0005 to 1: 14: 14: 6 Yes, more preferably 1: 0.2: 0.005: 0.001-1: 8: 8: 4, most preferably 1: 0.2: 0.01: 0.001-1: 3: 6: 1.

Below, the manufacturing method of the aqueous | water-based pharmaceutical composition of this invention is illustrated.
Various additives including amine, water-soluble polymer, surfactant and tonicity agent are added to purified water and dissolved by stirring. At this time, heated purified water can be used if necessary for dissolution. The angiotensin II receptor antagonist which is an active ingredient is added here, and it stirs well. After confirming that all components are dissolved and the chemical solution is clear, adjust the pH and make up with purified water. This aqueous solution is sterilized by filtration through a membrane filter and then filled into a plastic bottle or the like.

As said manufacturing method, the following preparation processes can be shown, for example.
Purified water with meglumine, monoethanolamine, 2-amino-2-methyl-1-propanol, diethanolamine or trometamol, polyvinylpyrrolidone K25, polyoxyethylene hydrogenated castor oil 60 or polysorbate 80, glycerin, and benzalkonium chloride The product was added to 80 mL of purified water, and dissolved by stirring. An angiotensin II receptor antagonist was added here, and it stirred until it melt | dissolved. After confirming that all the components were dissolved and the chemical solution became clear, the pH was adjusted. Next, it is made up with purified water, sterilized by filtration with a membrane filter, and then filled into a plastic bottle.

In addition to the production method described above, the aqueous pharmaceutical composition of the present invention can be prepared by the following production method.
Glycerin, benzalkonium chloride, polyoxyethylene hydrogenated castor oil 60 or polysorbate 80 was added to purified water and dissolved by stirring. To this, meglumine, monoethanolamine, 2-amino-2-methyl-1-propanol, diethanolamine or trometamol, polyvinylpyrrolidone K25 and an angiotensin II receptor antagonist were added and stirred until dissolved. After confirming that all components are dissolved and the chemical solution is clear, adjust the pH and make up with purified water. This aqueous solution is sterilized by filtration with a membrane filter and then filled into a plastic bottle.

[Comparative Examples 1-3]
A predetermined amount of meglumine, polyvinylpyrrolidone K25 or polyoxyethylene hydrogenated castor oil 60, a predetermined amount of glycerin, and a predetermined amount of benzalkonium chloride were added to 80 mL of purified water and dissolved. A predetermined amount of candesartan cilexetil was added and well stirred. Thereafter, 1 mol / L hydrochloric acid was added to adjust the pH. The volume was made up to 100 mL with purified water to obtain Comparative Examples 1 to 3. The compositions of Comparative Examples 1 to 3 are shown in Table 1.

According to the present invention, the following aqueous pharmaceutical composition can be prepared.

[Examples 1 to 9]
A predetermined amount of meglumine, monoethanolamine, 2-amino-2-methyl-1-propanol, diethanolamine or trometamol, a predetermined amount of polyvinylpyrrolidone K25, and a predetermined amount of polyoxyethylene hydrogenated castor oil 60 or polysorbate 80 depending on the formulation. Depending on the formulation, a predetermined amount of glycerin and, depending on the formulation, a predetermined amount of benzalkonium chloride were added to 80 mL of purified water and dissolved by stirring. A predetermined amount of candesartan cilexetil was added thereto and stirred until dissolved. After confirming dissolution, 1 mol / L hydrochloric acid was added to adjust the pH. Next, it made up to 100 mL with purified water, filtered with a membrane filter, and prepared Examples 1-9 which are the aqueous | water-based pharmaceutical composition of this invention. The compositions of Examples 1 to 9 are shown in Table 1.

[Examples 10 and 11]
A predetermined amount of methylcellulose (product name: METOLOSE (registered trademark) SM-4, manufactured by Shin-Etsu Chemical Co., Ltd.) or hypromellose (product name: METOLOSE (registered trademark) 65SH400, manufactured by Shin-Etsu Chemical Co., Ltd.) is 85 ° C. 80 mL of purified water heated to was added and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole was clear, it was left to return to room temperature. A predetermined amount of meglumine, a predetermined amount of polyvinylpyrrolidone K25, a predetermined amount of polyoxyethylene hydrogenated castor oil 60 or polysorbate 80, a predetermined amount of glycerin, and a predetermined amount of benzalkonium chloride were prepared in advance. It was added to a methylcellulose solution or a hypromellose solution and dissolved by stirring. A predetermined amount of candesartan cilexetil was added thereto and stirred until dissolved. After confirming dissolution, 1 mol / L hydrochloric acid was added to adjust the pH. Next, the volume was made up to 100 mL with purified water and filtered with a membrane filter to prepare Examples 10 and 11 which are aqueous pharmaceutical compositions of the present invention. The compositions of Examples 10 and 11 are shown in Table 2.

[Examples 12 to 20]
A predetermined amount of meglumine, a predetermined amount of polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, and depending on the formulation, polyvinyl alcohol 1000 (partially saponified type) or polyethylene glycol 4000, and a predetermined amount of polyoxyethylene hydrogenated castor oil 60 or Polysorbate 80, depending on the prescription, a predetermined amount of hydroxyethyl cellulose (NATROSOL®), sodium hyaluronate or sodium carboxymethyl cellulose, a predetermined amount of glycerin, and a predetermined amount of benzalkonium chloride in 80 mL of purified water Added and dissolved by stirring. A predetermined amount of candesartan cilexetil was added thereto and stirred until dissolved. After confirming dissolution, 1 mol / L hydrochloric acid or sodium dihydrogen phosphate was added to adjust the pH. Next, the volume was made up to 100 mL with purified water and filtered through a membrane filter to prepare Examples 12 to 20, which are aqueous pharmaceutical compositions of the present invention. The compositions of Examples 12-20 are listed in Table 2.

[Examples 21 to 31]
A predetermined amount of meglumine, a predetermined amount of polyvinylpyrrolidone K25, a predetermined amount of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, polyoxyl 40 stearate, tyloxapol, polyoxyethylene polyoxypropylene glycol (Pluronic (registered trademark) F68) A predetermined amount of glycerin and a predetermined amount of benzalkonium chloride were added to 80 mL of purified water, and dissolved by stirring. A predetermined amount of candesartan cilexetil was added thereto and stirred until dissolved. After confirming dissolution, 1 mol / L hydrochloric acid or sodium dihydrogen phosphate was added to adjust the pH. Next, the volume was made up to 100 mL with purified water and filtered with a membrane filter to prepare Examples 21 to 31 which are aqueous pharmaceutical compositions of the present invention. The compositions of Examples 21 to 31 are shown in Table 3.

[Examples 32-43]
A predetermined amount of meglumine or monoethanolamine, a predetermined amount of trometamol, a predetermined amount of polyvinylpyrrolidone K25, a predetermined amount of polyoxyethylene hydrogenated castor oil 60 or polysorbate 80, and a predetermined amount of glycerin or Propylene glycol, a predetermined amount of benzalkonium chloride, and depending on the formulation, a predetermined amount of epsilon aminocaproic acid, ethylenediaminetetraacetic acid disodium (hereinafter also referred to as “EDTA”) or sodium citrate are added to 80 mL of purified water. And dissolved by stirring. A predetermined amount of candesartan cilexetil was added thereto and stirred until dissolved. After confirming dissolution, 1 mol / L hydrochloric acid, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid or citric acid were added to adjust the pH. Next, the volume was made up to 100 mL with purified water and filtered with a membrane filter to prepare aqueous pharmaceutical compositions (Examples 32-43) of the present invention. The compositions of Examples 32-43 are shown in Table 4.

[Examples 44 to 55]
A predetermined amount of meglumine or monoethanolamine, a predetermined amount of trometamol, a predetermined amount of polyvinylpyrrolidone K25, a predetermined amount of benzalkonium chloride, and a predetermined amount of polyoxyethylene hydrogenated castor oil 60 depending on the formulation. Alternatively, polysorbate 80 and a predetermined amount of glycerin depending on the formulation were added to 80 mL of purified water, and dissolved by stirring. A predetermined amount of candesartan cilexetil, candesartan, azilsartan, valsartan, irbesartan, olmesartan medoxomil or telmisartan was added and stirred until dissolved. After confirming dissolution, 1 mol / L hydrochloric acid or sodium dihydrogen phosphate was added to adjust the pH. Next, the volume was made up to 100 mL with purified water and filtered through a membrane filter to prepare aqueous pharmaceutical compositions (Examples 44 to 55) of the present invention. The compositions of Examples 44 to 55 are shown in Table 5.

[Examples 56 to 58]
A predetermined amount of meglumine, a predetermined amount of polyvinylpyrrolidone K25, a predetermined amount of polyoxyethylene hydrogenated castor oil 60, and a predetermined amount of glycerin were added to 80 mL of purified water, and dissolved by stirring. A predetermined amount of candesartan cilexetil was added thereto and stirred until dissolved. After confirming dissolution, 1 mol / L hydrochloric acid was added to adjust the pH. Next, the volume was made up to 100 mL with purified water and filtered through a membrane filter to prepare aqueous pharmaceutical compositions (Examples 56 to 58) of the present invention. The compositions of Examples 56 to 58 are shown in Table 6.

By blending an amine and a water-soluble polymer, a slightly water-soluble angiotensin II receptor antagonist can be solubilized.
According to the clear aqueous pharmaceutical composition provided by the present invention, an angiotensin II receptor antagonist is used as an active ingredient as a liquid agent such as an ophthalmic composition, a nose composition, an ear composition, an injectable composition, and the like. Pharmaceutical compositions can be developed by new routes of administration. If local administration of a drug by a liquid agent becomes possible, it becomes possible to reach the required site at a high concentration and reduce systemic side effects. In addition, if used as an eye drop, it is predicted that the overturning stirring and fogging that occurs during each use as occurs with conventional suspension eye drops will be reduced, reducing patient burden and improving adherence. Be expected.

Claims (12)

Aqueous pharmaceutical composition comprising (A) angiotensin II receptor antagonist, (B) amine and (C) water-soluble polymer The aqueous pharmaceutical composition according to claim 1, further comprising (D) a surfactant. The aqueous pharmaceutical composition according to claim 1 or 2, further comprising (E) an isotonic agent. (A) The angiotensin II receptor antagonist comprises candesartan cilexetil, candesartan, valsartan, losartan potassium, olmesartan, olmesartan medoxomil, telmisartan, irbesartan, azilsartan, azilsartan medoxomil, and pharmacologically acceptable salts or derivatives thereof. The aqueous pharmaceutical composition according to any one of claims 1 to 4, comprising at least one selected from the group. The aqueous pharmaceutical composition according to any one of claims 1 to 4, wherein (A) the angiotensin II receptor antagonist is candesartan cilexetil. (B) at least one selected from the group consisting of meglumine, monoethanolamine, 2-amino-2-methyl-1-propanol, trometamol, diethanolamine, triethanolamine, glucosamine, triethylamine, lysine, arginine and histidine. An aqueous pharmaceutical composition according to any one of claims 1 to 5, (C) Water-soluble polymer is polyvinylpyrrolidone, The aqueous pharmaceutical composition of any one of Claims 1-6 (D) At least one surfactant selected from the group consisting of polyoxyethylene hydrogenated castor oil, polysorbate, polyoxyl stearate, tyloxapol, polyoxyethylene polyoxypropylene glycol, polyoxyethylene castor oil and benzalkonium chloride An aqueous pharmaceutical composition according to any one of claims 1 to 7 comprising (E) The isotonic agent contains at least one selected from the group consisting of glycerin, propylene glycol, mannitol, glucose, sorbitol, xylitol, sodium chloride and potassium chloride. Aqueous pharmaceutical composition (A) A method for producing an aqueous pharmaceutical composition comprising a step of mixing an angiotensin II receptor antagonist, (B) an amine, and (C) a water-soluble polymer. Furthermore, (D) The manufacturing method of the aqueous | water-based pharmaceutical composition of Claim 10 including the process of mixing surfactant. The method for producing an aqueous pharmaceutical composition according to claim 10 or 11, further comprising the step of (E) mixing an isotonic agent.