Aqueous suspension containing rebamipide or salt thereof and polymer

Abstract

To provide a rebamipide-containing aqueous suspension having similar properties to Mucosta(R) ophthalmic suspension UD2% without using PVA, which may react with borate ions to form a gel, as an additive.SOLUTION: An aqueous suspension containing rebamipide or a salt thereof and a silver salt or chlorobutanol, preferably further containing polyvinylpyrrolidone in an amount of 2%(w / v) or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous suspension containing rebamipide or a salt thereof and at least one polymer selected from the group consisting of carmellose sodium, dextran, and polyvinylpyrrolidone. [Background technology]

[0002] Dry eye is a disease that begins with the discomfort of dry, gritty eyes, but as it worsens, it can cause significant disruption to daily life. The number of dry eye patients is increasing year by year due to the arrival of an aging society and the increase in work using VDTs (video display terminals) such as computers.

[0003] The generic name of rebamipide is "2-(4-chlorobenzoylamino)-3-(2-quinolone-4-yl)propionic acid," and it is known to increase mucin production by increasing goblet cells in the eye, thereby preventing the decrease in mucin seen in dry eye. Furthermore, Ophthalmology, 119(12), 2471-2478 (2012) (Non-Patent Document 1) describes that administering an eye drop containing rebamipide improved the objective findings (corneal epithelial damage, etc.) and subjective symptoms of dry eye patients. In Japan, an eye drop containing 2% (w / v) rebamipide (free form) is used as a dry eye treatment drug (product name: Mucosta (登録商標) Eye drops UD 2%).

[0004] Mucosta (登録商標) The package insert for UD2% eye drops (Non-patent Document 2) states that Mucosta (登録商標)It is described that the ophthalmic solution UD2% contains a partially saponified polyvinyl alcohol as an additive. Furthermore, JP-A No. 2010-507566 (Patent Document 1) describes that by blending polyvinyl alcohol (PVA) together with rebamipide in an aqueous solution, rebamipide in the form of fine particles can be uniformly dispersed without using a special dispersing / suspending device, and further, the suspension state can be stably maintained without causing reaggregation of the fine particles of rebamipide.

[0005] On the other hand, Non-Patent Document 2 states that Mucosta (登録商標) It has been reported that serious side effects of UD 2% eye drops include lacrimal duct obstruction and dacryocystitis, and that in cases of lacrimal duct obstruction and dacryocystitis, white material may be observed in the lacrimal duct. Furthermore, Atarashii Ophthalmology, 32(12), 1741-1747 (2015) (Non-Patent Document 3) suggests that PVA has the property of reacting with borate ions to form a gel. Many eye drops on the market in Japan contain boric acid as an additive. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2010-507566 [Non-patent literature]

[0007] [Non-Patent Document 1] Ophthalmology, 119(12), 2471-2478 (2012) [Non-patent document 2] Mucosta (registered trademark) Ophthalmic Solution UD 2% Package Insert [Non-patent document 3] New Ophthalmology, 32(12), 1741-1747 (2015) Summary of the Invention [Problem to be solved by the invention]

[0008] The object of the present invention is to provide a method for producing Mucosta without using PVA as an additive. (登録商標) The object of the present invention is to prepare an aqueous suspension containing rebamipide having properties similar to those of UD2% eye drops. [Means for solving the problem]

[0009] As a result of intensive research conducted by the present inventors to solve the above problems, it has been found that the use of at least one polymer selected from the group consisting of carmellose sodium, dextran, and polyvinylpyrrolidone instead of PVA can effectively prevent the formation of mucosal vesicles. (登録商標) We successfully prepared an aqueous suspension containing rebamipide with properties similar to those of UD2% eye drops.

[0010] That is, the present invention relates to the following: (1) An aqueous suspension containing rebamipide or a salt thereof and a polymer, wherein the polymer is at least one compound selected from the group consisting of carmellose sodium, dextran, and polyvinylpyrrolidone (hereinafter also referred to as "this aqueous suspension").

[0011] (2) The aqueous suspension according to (1), which does not contain polyvinyl alcohol. (3) The aqueous suspension according to (1) or (2), wherein the polymer is polyvinylpyrrolidone.

[0012] (4) The aqueous suspension according to (3), wherein the concentration of polyvinylpyrrolidone is 2% (w / v) or less.

[0013] (5) The aqueous suspension according to (4), further containing a carboxyl vinyl polymer. (6) The aqueous suspension according to (5), wherein the concentration of the carboxyl vinyl polymer is 0.05 to 0.2% (w / v).

[0014] (7) The aqueous suspension according to any one of (1) to (6), wherein the K value of polyvinylpyrrolidone is 17 to 60.

[0015] (8) The aqueous suspension according to any one of (1) to (7), wherein the K value of polyvinylpyrrolidone is 30.

[0016] (9) The aqueous suspension according to any one of (1) to (8), which is administered by instillation into the eye.

[0017] (10) The aqueous suspension according to any one of (1) to (9), wherein the rebamipide or a salt thereof is rebamipide (free form).

[0018] (11) The aqueous suspension according to any one of (1) to (10), wherein the concentration of rebamipide or a salt thereof is 2% (w / v).

[0019] (12) The aqueous suspension according to any one of (1) to (11), wherein the average particle size of rebamipide is 0.1 to 3 μm.

[0020] (13) Dynamic viscosity is 1.8 to 3.0 mm 2 The aqueous suspension according to any one of (1) to (12), wherein the total amount of the aqueous suspension is 1 / s.

[0021] (14) The aqueous suspension according to any one of (1) to (13), further containing silver nitrate.

[0022] (15) An aqueous suspension containing 2% (w / v) rebamipide (free form), 2% (w / v) or less of polyvinylpyrrolidone, carboxyvinyl polymer, and silver nitrate, but not containing polyvinyl alcohol, wherein the average particle size of rebamipide is 0.1 to 3 μm, the K value of polyvinylpyrrolidone is 30, and the kinematic viscosity is 1.8 to 3.0 mm. 2 / s and is an aqueous suspension administered by instillation into the eye.

[0023] (16) The aqueous suspension according to any one of (1) to (15), which is administered by instillation to an eye wearing a soft contact lens. [Effects of the Invention]

[0024] According to the present invention, Mucosta can be produced without using PVA. (登録商標) It is possible to provide an aqueous suspension containing rebamipide having properties similar to those of the ophthalmic solution UD2%.

[0025] Furthermore, according to the present invention, the commercially available "Mucosta (登録商標) It is possible to provide an aqueous suspension containing rebamipide that is expected to be less likely to cause side effects such as lacrimal duct obstruction and dacryocystitis, which are observed in "Ophthalmic Solution UD 2%." It is also possible to provide a multi-dose aqueous suspension containing rebamipide that can be used multiple times. DETAILED DESCRIPTION OF THE INVENTION

[0026] Rebamipide used in the present invention is a compound represented by the following formula:

[0027] [ka]

[0028] The chemical name of rebamipide used in the present invention is (2RS)-2-(4-Chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid.

[0029] Rebamipide used in the present invention can be prepared by conventional methods in the field of organic synthetic chemistry, and is commercially available from Sigma as rebamipide hydrate.

[0030] The salt of rebamipide used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid, salts with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid. salts with halogen ions such as bromide ion, chloride ion, and iodide ion; salts with alkali metals such as lithium, sodium, and potassium; salts with alkaline earth metals such as calcium and magnesium; metal salts with iron and zinc; salts with ammonia; and salts with organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

[0031] In the present invention, solvates of rebamipide such as rebamipide hydrate are included in "rebamipide or a salt thereof."

[0032] In the present invention, "rebamipide or a salt thereof" is preferably rebamipide (free form).

[0033] In the present invention, when rebamipide or a salt thereof has geometric or optical isomers, such isomers or salts thereof are also included in the scope of the present invention. In addition, when rebamipide or a salt thereof has proton tautomerism, such tautomers or salts thereof are also included in the scope of the present invention.

[0034] In the present invention, when rebamipide or a salt thereof (including a hydrate or solvate) has crystalline polymorphs and crystalline polymorphic systems, these crystalline polymorphs and crystalline polymorphic systems (crystalline polymorphic systems) are also included within the scope of the present invention. Here, the crystalline polymorphic systems (crystalline polymorphic systems) refer to the individual crystalline forms at each stage and the entire process when the crystalline form changes depending on the conditions and states of production, crystallization, storage, etc. of the crystals (including the state after formulation).

[0035] The concentration of rebamipide or a salt thereof contained in the aqueous suspension is preferably 0.5 to 5% (w / v), more preferably 1 to 3% (w / v), and even more preferably 2% (w / v).

[0036] The aqueous suspension contains at least one polymer selected from the group consisting of carmellose sodium, dextran, and polyvinylpyrrolidone.

[0037] In the present invention, carmellose sodium refers to a cellulose derivative also known as sodium carboxymethylcellulose.

[0038] In the present invention, dextran refers to dextran having various molecular weights. Examples of dextran contained in the aqueous suspension include dextran 40 and dextran 70, with dextran 70 being particularly preferred.

[0039] In the present invention, polyvinylpyrrolidone refers to a polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone. Polyvinylpyrrolidone, also known as povidone, is generally used as a thickening agent.

[0040] The K value of the polyvinylpyrrolidone contained in the present aqueous suspension is preferably 17 or more, more preferably 17 to 90, even more preferably 17 to 60, and most preferably 30. As will be described later, a K value of 30 is synonymous with a K value in the range of 27 to 32.4.

[0041] Examples of polyvinylpyrrolidone contained in the present aqueous suspension include polyvinylpyrrolidone K15 (PVP K15), polyvinylpyrrolidone K17 (PVP K17), polyvinylpyrrolidone K25 (PVP K25), polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone K40 (PVP K40), polyvinylpyrrolidone K50 (PVP K50), polyvinylpyrrolidone K60 (PVP K60), polyvinylpyrrolidone K70 (PVP K70), polyvinylpyrrolidone K80 (PVP K80), polyvinylpyrrolidone K85 (PVP K85), polyvinylpyrrolidone K90 (PVP K90), and polyvinylpyrrolidone K120 (PVP K120). Polyvinylpyrrolidone K40 (PVP K50), polyvinylpyrrolidone K50 (PVP K50), polyvinylpyrrolidone K60 (PVP K60) are preferred, and polyvinylpyrrolidone K30 (PVP K30) is particularly preferred.

[0042] The K value of polyvinylpyrrolidone is a viscosity characteristic value that correlates with molecular weight, and is calculated by applying the relative viscosity value (25°C) measured with a capillary viscometer to the following Fikentscher formula (1).

[0043]

number

[0044] In the formula (1), ηrel is the relative viscosity of the aqueous polyvinylpyrrolidone solution to water, and c is the concentration (%) of polyvinylpyrrolidone in the aqueous polyvinylpyrrolidone solution.

[0045] Here, the K value is 90 to 108% of the indicated K value in accordance with the description of the K value in the Japanese Pharmacopoeia, Seventeenth Edition, for "Povidone." For example, "K30" refers to a viscosity characteristic value (K value) calculated by applying the above formula (1) in the range of 27 to 32.4.

[0046] The aqueous suspension may contain one type of polyvinylpyrrolidone alone, or two or more types of polyvinylpyrrolidone with different K values ​​may be used in any combination.

[0047] The concentration of the polymer contained in the aqueous suspension is preferably 0.1 to 10% (w / v), more preferably 1 to 10% (w / v), and most preferably 1 to 3% (w / v).

[0048] The safety of polyvinylpyrrolidone in ophthalmic solutions at concentrations exceeding 2% (w / v) has not been clinically confirmed. While this does not preclude the aqueous suspension from containing polyvinylpyrrolidone at a concentration exceeding 2% (w / v), it may be a reason for limiting the concentration of polyvinylpyrrolidone contained in the aqueous suspension to 2% (w / v) or less. Therefore, when the polymer contained in the aqueous suspension is polyvinylpyrrolidone, its concentration is preferably 0.1 to 2% (w / v), more preferably 0.5 to 2% (w / v), particularly preferably 1 to 2% (w / v), and most preferably 2% (w / v).

[0049] When the concentration of polyvinylpyrrolidone contained in the aqueous suspension is set to 2% (w / v) or less, a carboxyvinyl polymer can be added to increase the dynamic viscosity of the aqueous suspension.

[0050] In the present invention, the term "carboxyvinyl polymer" refers to a polymer of acrylic acid, also known as carbomer. Carboxylvinyl polymers are commercially available, for example, CARBOPOL® from Lubrizol. (登録商標) 981NF, CARBOPOL(登録商標) 974PNF, CARBOPOL (登録商標) 971PNF and others are commercially available.

[0051] The concentration of the carboxyvinyl polymer contained in this aqueous suspension is preferably 0.01 to 1% (w / v), more preferably 0.03 to 0.5% (w / v), even more preferably 0.05 to 0.3% (w / v), and most preferably 0.05 to 0.2% (w / v).

[0052] In the present invention, aqueous suspension means a suspension based on water. The average particle size (D50) of rebamipide or a salt thereof contained in the aqueous suspension of the present invention is preferably 0.01 to 10 μm, more preferably 0.05 to 5 μm, even more preferably 0.1 to 3 μm, and most preferably 0.5 to 1 μm. The average particle size of rebamipide contained in the aqueous suspension is calculated by laser diffraction. The method for measuring the average particle size of rebamipide is also disclosed in JP-A-2010-507566, which was explained in the Background Art section.

[0053] The aqueous suspension of the present invention preferably does not contain polyvinyl alcohol (PVA). Here, "does not contain polyvinyl alcohol" literally means that it does not contain any polyvinyl alcohol (PVA) at all, or that it does not substantially contain polyvinyl alcohol. Note that "polyvinyl alcohol" includes partially saponified polyvinyl alcohol.

[0054] This aqueous suspension is administered topically to the eye several times a day for the treatment or alleviation of dry eye or its associated symptoms, preferably one drop at a time, four times a day.

[0055] The aqueous suspension can be administered topically to the eye, but is preferably administered as eye drops filled in an eye dropper container.

[0056] The dynamic viscosity of the aqueous suspension is preferably 1.0 to 10.0 mm 2 / s, 1.5 to 5.0 mm 2 / s is more preferable, and 1.8 to 3.0 mm 2 / s is more preferable, and 2.0 to 2.5 mm 2 The kinematic viscosity is most preferably 1 / s. The kinematic viscosity is measured using an Ubbelohde viscometer (measurement temperature: 25.0°C).

[0057] The aqueous suspension can be prepared as a unit dose eye drop for single use, or can be prepared as a multi-dose eye drop for multiple use by adding a preservative.

[0058] Preservatives that can be added to the aqueous suspension include silver or silver salts, benzalkonium chloride, chlorobutanol, etc., with silver salts being particularly preferred.

[0059] In the present invention, silver salts include, for example, silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, and silver protein, but preferably silver nitrate.

[0060] The concentration of silver or silver salt contained in the aqueous suspension is preferably greater than 0.000005% (w / v), more preferably 0.000006 to 0.0002% (w / v), even more preferably 0.000007 to 0.00015% (w / v), particularly preferably 0.000008 to 0.00012% (w / v), and most preferably 0.000009 to 0.0001% (w / v).

[0061] When the silver salt added to the present aqueous suspension is silver nitrate, the concentration of silver nitrate contained in the present aqueous suspension is preferably more than 0.00001% (w / v), more preferably 0.000011 to 0.0001% (w / v), even more preferably 0.000015 to 0.00005% (w / v), particularly preferably 0.00002 to 0.00005% (w / v), and most preferably 0.00002 to 0.00004% (w / v).

[0062] The aqueous suspension may contain additives other than preservatives and at least one polymer selected from the group consisting of carmellose sodium, dextran, and polyvinylpyrrolidone, such as buffering agents (e.g., sodium citrate, sodium phosphate, sodium acetate, and epsilon-aminocaproic acid); isotonicity adjusting agents (e.g., sodium chloride, potassium chloride, and concentrated glycerin); and pH adjusters (e.g., hydrochloric acid and sodium hydroxide).

[0063] The pH of the aqueous suspension is preferably 4.0 to 7.0, more preferably 5.0 to 7.0, and most preferably 5.5 to 6.5.

[0064] The osmotic pressure ratio of the present aqueous suspension is preferably 0.5 to 1.5, more preferably 0.7 to 1.3, and most preferably 0.9 to 1.1.

[0065] The aqueous suspension can be instilled into eyes wearing hard or soft contact lenses.

[0066] Soft contact lenses (SCLs) are classified into four groups in accordance with Notification No. 645 of the Pharmaceutical and Medical Affairs Agency, dated March 31, 1999, entitled "Handling of documents to be attached when applying for approval to manufacture (import) soft contact lenses and soft contact lens disinfectants." Namely, they are classified into Group I (non-ionic with a water content of less than 50%), Group II (non-ionic with a water content of 50% or more), Group III (ionic with a water content of less than 50%), and Group IV (ionic with a water content of 50% or more), with SCLs being classified as ionic if the molar percentage of monomers containing anions among the constituent monomers of the raw material polymer is 1% or more, and non-ionic if the molar percentage is less than 1%. Examples of soft contact lenses include soft contact lenses whose main component is 2-hydroxyethyl methacrylate (HEMA), (polyethylene glycol) monomethacrylate (PEGMA), glycerol methacrylate (GMA), N,N-dimethylacrylamide (DMA), vinyl alcohol (VA), N-vinylpyrrolidone (NVP or VP), methacrylic acid (MAA), fluorine-containing methacrylate compounds, silicon-containing methacrylate compounds, silicone hydrogel, cycloalkyl methacrylate, or the like.

[0067] In the present invention, "administered by instillation to eyes wearing soft contact lenses" means that the aqueous suspension can be administered by instillation to the eyes while the soft contact lenses are being worn. Note that, since benzalkonium chloride is known to adsorb to soft contact lenses and deform them, it is preferable that "the aqueous suspension to be administered by instillation to eyes wearing soft contact lenses" does not contain benzalkonium chloride as a preservative.

[0068] The following are test results and formulation examples using this aqueous suspension, but these examples are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention. [Example]

[0069] [Test 1] We investigated whether this aqueous suspension would gel in the presence of boric acid.

[0070] (Sample preparation method) Formulation 1-1: 0.146 g of sodium citrate hydrate, 0.62 g of sodium chloride, 0.18 g of potassium chloride, 0.11 g of carboxyvinyl polymer, 2.0 g of polyvinylpyrrolidone, and 0.00004 g of silver nitrate were dissolved in water, 2.0 g of rebamipide was added, and the mixture was suspended with stirring. The pH was adjusted to 6.9, and water was added to make 100 mL.

[0071] Comparative Formulation 1-1: Commercially available "Mucosta (登録商標) Eye drops UD 2% were used. Comparative formulation 1-2 (artificial tears): 0.85 g of sodium chloride, 0.4 g of potassium chloride, and 0.022 g of calcium chloride hydrate were dissolved in water to make 100 mL.

[0072] Boric acid-containing solution: 0.5 g of boric acid, 0.4 g of sodium chloride, and 0.1 g of potassium chloride were dissolved in water, the pH was adjusted to 7.0, and water was added to make up to 100 mL.

[0073] (Test Method) 0.35 mL of Formulation 1-1 was placed in a beaker, and 1 mL of boric acid-containing solution was added and mixed. The solution was scooped up with a spatula, and if a stringy gel was observed, it was judged to have "gelled." The same procedure was performed on Comparative Formulation 1-1 and artificial tears.

[0074] (result) The test results are shown in Table 1. No gelation was observed in Formulation 1-1 and Comparative Formulation 1-2 (artificial tears), but thread-like gelation was observed in Comparative Formulation 1-1.

[0075] [Table 1]

[0076] (Consideration) As described in the Background Art section, Mucosta (登録商標)Side effects such as lacrimal duct obstruction and dacryocystitis have been observed with UD 2% eye drops, and the cause of these is thought to be Mucosta (登録商標) It has been pointed out that the PVA contained in UD 2% eye drops reacts with the borate ions contained in other eye drops to form a gel. (登録商標) While it was confirmed that UD2% eye drops reacted with borate ions to form a gel, this effect was not observed in the aqueous suspension, so it is expected that the aqueous suspension will be less likely to cause side effects such as lacrimal duct obstruction and dacryocystitis.

[0077] [Test 2] Mucosta (登録商標) The particle size (D50) of rebamipide contained in aqueous suspensions of partially saponified polyvinyl alcohol used in UD 2% eye drops and in each polymer other than PVA was measured and compared.

[0078] (Sample preparation method) Each solution was prepared by dissolving the components shown in Table 2 in water at a soluble concentration range of 0.5% (w / v) to 1% (w / v). Rebamipide was added to each solution to give a final concentration of 2% (w / v) to prepare an aqueous suspension.

[0079] (Test Method) The particle size distribution was measured using a laser diffraction particle size distribution analyzer, and the particle size (D50) of rebamipide was compared.

[0080] (result) The measurement results are shown in Table 2. (登録商標) When aqueous suspensions of rebamipide were prepared using partially saponified polyvinyl alcohol, which is used in UD 2%, the D50 of rebamipide was approximately 1 μm. On the other hand, when aqueous suspensions of rebamipide were prepared using many polymers other than PVA, the D50 of rebamipide was on the order of several tens to several hundred μm. However, when sodium carmellose, dextran, or polyvinylpyrrolidone was used, the D50 of rebamipide was successfully reduced to less than 3 μm.

[0081] [Table 2]

[0082] (Consideration) The particle size of rebamipide aqueous suspensions prepared using carmellose sodium, dextran 70, or polyvinylpyrrolidone instead of PVA was (登録商標) It was shown that the effect was comparable to that of UD 2% eye drops. In particular, when polyvinylpyrrolidone K30 (povidone K30) was used instead of PVA, the effect was significantly greater than that of Mucosta. (登録商標) It was suggested that the particle size of rebamipide obtained was almost the same as that of the UD 2% ophthalmic solution.

[0083] [Test 3] The viscosity of the aqueous suspension was measured using the (登録商標) The polymers and concentrations that could be made equivalent to the UD 2% eye drops were compared. The particle size distribution was also measured.

[0084] (Sample preparation method) Formulation 3-1: Sodium citrate hydrate 0.15 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymer (CARBOPOL (登録商標) 0.11 g of 971PNF, 2 g of polyvinylpyrrolidone K30, and 0.00003 g of silver nitrate were dissolved in water, 2 g of rebamipide was added, and the mixture was stirred and suspended. The pH was adjusted to 5.9, and water was added to make 100 mL.

[0085] Formulations 3-2 to 3-6: Prepared in the same manner as formulation 3-1 according to the formulation table in Table 3. Comparative formulation: commercially available "Mucosta (登録商標) Eye drops UD 2% were used.

[0086] (Test Method) The kinematic viscosity was measured using an Ubbelohde viscometer in accordance with "Japanese Pharmacopoeia General Test Methods, Viscosity Measurement Method No. 1." The particle size distribution of rebamipide was measured using the aforementioned laser diffraction particle size distribution analyzer.

[0087] (result) The measurement results are shown in Table 3. By setting the concentration of polyvinylpyrrolidone at 6% (w / v), the commercially available "Mucosta (登録商標) It was possible to prepare an aqueous rebamipide suspension with a viscosity equivalent to that of the commercially available "Mucosta Eye Drops UD 2%." Furthermore, when the concentration of polyvinylpyrrolidone was 2% (w / v) or less, the addition of carboxyl vinyl polymer resulted in a viscosity equivalent to that of the commercially available "Mucosta Eye Drops UD 2%." (登録商標) It was confirmed that an aqueous suspension of rebamipide having a viscosity equivalent to or greater than that of "UD 2% Ophthalmic Solution" was obtained, while the particle size of rebamipide was not affected at all.

[0088] [Table 3]

[0089] (Consideration) The results of this test show that by adding polyvinylpyrrolidone at a concentration of 6% (w / v) or more, the commercially available "Mucosta (登録商標) It was suggested that it was possible to prepare an aqueous rebamipide suspension with a viscosity and particle size equivalent to that of "Mucosta Eye Drops UD 2%." On the other hand, when the concentration of polyvinylpyrrolidone was set to 2% or less, which has been clinically confirmed as safe, the addition of carboxyl vinyl polymer resulted in a viscosity and particle size equivalent to that of the commercially available "Mucosta Eye Drops UD 2%." (登録商標) This suggests that an aqueous rebamipide suspension with a viscosity and particle size equivalent to those of the 2% UD ophthalmic solution can be prepared. Considering that, as shown in Test 2, when an aqueous rebamipide suspension is prepared using only a carboxyvinyl polymer, the D50 of rebamipide is on the order of several tens to several hundreds of μm, it is a surprising result that the addition of a carboxyvinyl polymer had no effect on the particle size of rebamipide.

[0090] [Test 4] The average particle size of rebamipide contained in this aqueous suspension is (登録商標) It was compared with that of UD2% eye drops.

[0091] (Sample preparation method) Formulation 4-1: Sodium citrate hydrate 0.146 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymer (CARBOPOL (登録商標) 0.11 g of 971PNF, 2 g of polyvinylpyrrolidone K30, and 0.00004 g of silver nitrate were dissolved in water, 2 g of rebamipide was added, and the mixture was stirred and suspended. The pH was adjusted to 5.9, and water was added to make 100 mL.

[0092] Comparative formulation: commercially available "Mucosta (登録商標) Eye drops UD 2% were used. (Test Method) The particle size distribution was measured using a laser diffraction particle size distribution measuring device.

[0093] (result) The measurement results are shown in Table 4. The particle size distribution was (登録商標) This was within the range of "eye drops UD 2%".

[0094] [Table 4]

[0095] (Consideration) The particle size distribution of this aqueous suspension is the same as that of the commercially available (登録商標) As mentioned above, this aqueous suspension is within the range of "Mucosta ophthalmic solution UD 2%." (登録商標) Therefore, this aqueous suspension is considered to have a similar dynamic viscosity to "Mucosta Ophthalmic Solution UD 2%." (登録商標) It is expected to have the same therapeutic effect as UD2% eye drops.

[0096] The therapeutic effect on dry eye can be evaluated by tests using animal models of dry eye. (登録商標) It has been confirmed that it has the same therapeutic effect as UD2% eye drops.

[0097] [Test 5] The physicochemical stability of rebamipide contained in this aqueous suspension was evaluated by the Mucosta (登録商標) It was compared with that of UD2% eye drops.

[0098] (Sample preparation method) Formulation 5-1: Sodium citrate hydrate 0.146 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymer (CARBOPOL (登録商標) 0.11 g of 971PNF, 2 g of polyvinylpyrrolidone K30, and 0.00004 g of silver nitrate were dissolved in water, 2 g of rebamipide was added, and the mixture was stirred and suspended. The pH was adjusted to 5.9, and water was added to make 100 mL.

[0099] Comparative formulation: commercially available "Mucosta (登録商標) Eye drops UD 2% were used. (Test Method) Five mL of each of Formulation 5-1 and the comparative formulation was placed in an eye dropper container and stored at 60°C for two weeks. They were also stored at 40°C for two and three months. The physicochemical properties before and after storage were evaluated using the following test items and measurement methods.

[0100] The pH, viscosity, particle size, and redispersibility (formulation 5-1 only) were measured. pH: Measured according to the pH measurement method of the Japanese Pharmacopoeia General Test Method. Viscosity: For the comparative formulation, the viscosity was measured using a cone-and-plate viscometer in accordance with "Japanese Pharmacopoeia General Test Method, Viscosity Measurement Method, Method 2." For formulation 5-1, the kinematic viscosity was measured using an Ubbelohde viscometer in accordance with "Japanese Pharmacopoeia General Test Method, Viscosity Measurement Method, Method 1." Particle size: The particle size distribution was measured using a laser diffraction particle size distribution analyzer. Redispersibility: Hold the bottle horizontally between your thumb and index finger, shake it back and forth for 15 seconds, and if there is no visible adhesion to the bottle, the redispersibility is considered to be good.

[0101] (result) The measurement results are shown in Table 5. No changes were observed in any of the test items before and after storage, and the drug was stable.(登録商標) A decrease in pH was observed for Eye Drops UD 2%, but no decrease in pH was observed for Formulation 5-1.

[0102] [Table 5]

[0103] (Consideration) The physicochemical stability of Formulation 5-1 was compared with that of the commercially available "Mucosta (登録商標) It was equivalent to UD 2% eye drops.

[0104] [Test 6] Commercially available "Mucosta (登録商標) "UD 2% Eye Drops" is a unit dose eye drop that can be used once. However, multi-dose eye drops that contain preservatives and can be used multiple times are generally more convenient. Therefore, we searched for preservatives that can be incorporated into a 2% rebamipide aqueous suspension.

[0105] (Sample preparation method) Comparative Formulation 6-1: Commercially available "Mucosta (登録商標) Eye drops UD 2% were used.

[0106] Comparative Formulation 6-2: Comparative Formulation 6-2 was prepared according to the formulation shown in Table 6. Specifically, 0.15 g of sodium citrate hydrate, 0.72 g of sodium chloride, 0.18 g of potassium chloride, 1 g of partially saponified polyvinyl alcohol, and 0.01 g of chlorhexidine gluconate were dissolved in water, 2 g of rebamipide was added, and the mixture was stirred and suspended. The pH was adjusted to 6.0, and water was added to make 100 mL.

[0107] Comparative Formulations 6-3 to 6-12: Prepared according to the formulations shown in Tables 6 and 7 in the same manner as Comparative Formulation 6-2.

[0108] (Test Method) The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. In this test, all or part of Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus braziliensis (A. braziliensis) were used as test bacteria. The content of chlorhexidine gluconate was measured by the "Japanese Pharmacopoeia High Performance Liquid Chromatography Method."

[0109] (result) The measurement results are shown in Tables 6 and 7. Only the rebamipide-containing aqueous suspensions containing chlorobutanol or silver nitrate passed the preservative effectiveness test.

[0110] [Table 6]

[0111] [Table 7]

[0112] (Consideration) Chlorhexidine gluconate is an excellent preservative because it can be used in eyes wearing soft contact lenses, but it was found to be unsuitable as a preservative for use in aqueous suspensions containing rebamipide. This is thought to be because the amount of chlorhexidine gluconate dissolved in the suspension ophthalmic solution was only about 3% of the total amount, so it formed a complex with rebamipide and precipitated, and there was not enough of it to exert its preservative effect.

[0113] After examining various preservatives, it was suggested that silver nitrate and chlorobutanol were suitable preservatives for the aqueous suspension.

[0114] [Test 7] The effect of various concentrations of silver nitrate on the preservative efficacy of the aqueous suspension and the stability of silver nitrate in the aqueous suspension were evaluated.

[0115] (Sample preparation method) Formulation 7-1: Formulation 7-1 was prepared according to the formulation shown in Table 8. Specifically, 0.146 g of sodium citrate hydrate, 0.65 g of sodium chloride, 0.18 g of potassium chloride, 2 g of polyvinylpyrrolidone K30, carboxyvinyl polymer (CARBOPOL (登録商標) 0.11 g of 971PNF and 0.00004 g of silver nitrate were dissolved in water, 2 g of rebamipide was added, and the mixture was stirred and suspended. The pH was adjusted to 5.9, and water was added to make 100 mL.

[0116] Formulations 7-2-7 to 7-2-4: Prepared in the same manner as formulation 7-1 according to the formulations shown in Table 8. (Test Method) <Preservative effectiveness test> The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. The test bacteria used in this test were Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus braziliensis (A. braziliensis).

[0117] <Stability test> Five mL of each of Formulations 7-1 and 7-3 was placed in an eye dropper container and stored at 40°C for three months or under light exposure of 1.2 million lx·hr. The silver nitrate content in the solution before and after storage was measured using the Japanese Pharmacopoeia inductively coupled plasma mass spectrometry method.

[0118] (Test results) The test results are shown in Tables 8 and 9. It was confirmed that the aqueous suspension containing 0.00002% (w / v) or more of silver nitrate passed the preservative effectiveness test. Furthermore, no change in the silver nitrate concentration in the aqueous suspension was observed during the storage period.

[0119] [Table 8]

[0120] [Table 9]

[0121] (Consideration) It was shown that by adding silver nitrate as a preservative, this aqueous eye drop can be commercialized as a multi-dose eye drop that can be instilled multiple times.

[0122] [Test 8] The effect of this aqueous suspension on the physical properties of soft contact lenses was evaluated.

[0123] (Sample preparation method) Comparative formulation: commercially available "Mucosta (登録商標) Eye drops UD 2% were used.

[0124] Formulation 8-1: Formulation 8-1 was prepared according to the formulation shown in Table 10. Specifically, 0.146 g of sodium citrate hydrate, 0.65 g of sodium chloride, 0.18 g of potassium chloride, 1 g of polyvinylpyrrolidone K30, 0.5 g of methylcellulose, and 0.0000473 g of silver nitrate were dissolved in water, 2 g of rebamipide was added, and the mixture was suspended with stirring. The pH was adjusted to 5.9, and water was added to make 100 mL.

[0125] [Table 10]

[0126] (Test Method) Soft contact lenses (2-week Acuvue) were immersed in saline and their physical properties (diameter, base curve) were measured. The lenses were immersed in the comparative formulation or formulation 8-1 for 4 hours, and their physical properties (diameter, base curve) were measured again. The change in the physical properties (diameter, base curve) was calculated using the following formula.

[0127] Amount of change = Measurement value after immersion or re-immersion in chemical solution - Measurement value when immersed in saline <Unit of change> mm: diameter, base curve (Test results) After soaking in prescription 8-1, the soft contact lenses showed a decrease in diameter and base curve, but the amount of change in both was equal to or less than that of the comparison prescription.Furthermore, subsequent soaking in saline returned the lenses to within the standards for corrective contact lenses (Table 13) of Ministry of Health, Labour and Welfare Notification No. 349.

[0128] [Table 11]

[0129] [Table 12]

[0130] [Table 13]

[0131] (Consideration) Mucosta (登録商標) The UD2% eye drops can be administered to eyes wearing soft contact lenses. (登録商標) The change was within the range of the UD2% eye drop solution, demonstrating that this aqueous suspension can be administered by instillation to eyes wearing soft contact lenses. [Industrial Applicability]

[0132] According to the present invention, Mucosta can be produced without using polyvinyl alcohol. (登録商標) It is possible to provide an aqueous suspension containing rebamipide having properties similar to those of the ophthalmic solution UD2%.

Claims

1. An aqueous suspension containing rebamipide or a salt thereof and a silver salt or chlorobutanol.

2. 2. The aqueous suspension of claim 1, which contains polyvinylpyrrolidone.

3. 3. The aqueous suspension of claim 2, wherein the concentration of polyvinylpyrrolidone is 2% (w / v) or less.

4. 4. The aqueous suspension according to claim 1, wherein the average particle size of rebamipide is 0.1 to 3 μm.

5. 5. Aqueous suspension according to any one of claims 2 to 4, wherein the K value of polyvinylpyrrolidone is from 17 to 60.

6. 6. Aqueous suspension according to any one of claims 2 to 5, wherein the polyvinylpyrrolidone has a K value of 30.

7. The aqueous suspension according to any one of claims 1 to 6, which is administered by instillation into the eye.

8. 8. The aqueous suspension according to claim 1, wherein the rebamipide or a salt thereof is rebamipide (free form).

9. 9. The aqueous suspension according to claim 1, wherein the concentration of rebamipide or a salt thereof is 2% (w / v).

10. Dynamic viscosity is 1.8 to 3.0 mm ２ 10. The aqueous suspension according to claim 1, wherein the total weight of the suspension is 10 ...

11. 2. The aqueous suspension of claim 1, wherein the silver salt is silver nitrate.

12. 12. The aqueous suspension according to claim 1, which is administered by instillation to an eye wearing a soft contact lens.

13. 13. The aqueous suspension according to any one of claims 1 to 12, which is not intended for use with eye drops containing borate ions.

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