JP2022050562A - Aqueous suspension comprising rebamipide or salt thereof and polymer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a rebamipide-containing aqueous suspension having properties similar to a Mucosta ^(TM) ophthalmic suspension UD2% without the use of PVA as an additive.

SOLUTION: Provided is an aqueous suspension comprising rebamipide or a salt thereof and at least one polymer selected from the group consisting of sodium carmellose, dextran, and polyvinylpyrrolidone.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

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 sodium carmellose, dextran and polyvinylpyrrolidone.

Dry eye is a disease that begins with unpleasant symptoms such as dry eyes and rumbling, and when it worsens, it causes a great deal of trouble in daily life. The number of dry eye patients is increasing year by year with the advent of an aging society and the increase in VDT (video display tertiary) work such as personal computers.

The generic name for rebamipide is "2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) propionic acid", which increases mucin production by increasing the number of goblet cells in the eye. It is known to prevent the decrease in mucin found in dry eye. Furthermore, in Ophthalmology, 119 (12), 2471-2478 (2012) (Non-Patent Document 1), objective findings (corneal epithelial disorders, etc.) of dry eye patients were obtained by instilling eye drops containing rebamipide. , It is stated that the subjective symptoms have improved. In Japan, eye drops containing rebamipide (free form) at a concentration of 2% (w / v) are used as a therapeutic agent for dry eye (product name: Mucosta ^{(registered trademark)} ophthalmic solution UD 2%).

Mucosta ^{(registered trademark)} ophthalmic solution UD2% The package insert (Non-Patent Document 2) describes that Mucosta ^{(registered trademark)} ophthalmic solution UD2% contains polyvinyl alcohol partially saponified product as an additive. Further, in Japanese Patent Application Laid-Open No. 2010-507566 (Patent Document 1), by blending polyvinyl alcohol (PVA) together with rebamipide in an aqueous solution, the state of fine particles is obtained without using a special dispersion / suspension device. It is described that the rebamipide of the above can be uniformly dispersed, and the suspended state can be stably maintained without causing the reaggregation of the fine particles of the rebamipide.

On the other hand, in Non-Patent Document 2, lacrimal duct obstruction and lacrimal pouchitis may appear as serious side effects of Mucosta ^{(registered trademark)} ophthalmic solution UD2%, and tears in cases where lacrimal duct obstruction and lacrimal pouchitis are observed. It is stated that white substances may be found in Hokkaido. Furthermore, New Ophthalmology, 32 (12), 1741-1747 (2015) (Non-Patent Document 3) suggests that PVA has the property of reacting with borate ions to gel. Many of the eye drops on the market in Japan contain boric acid as an additive.

Special Table 2010-507566 Gazette

Ophthalmology, 119 (12), 2471-2478 (2012) Mucosta® Eye Drops UD2% Package Insert New Ophthalmology, 32 (12), 1741-1747 (2015)

An object of the present invention is to prepare a rebamipide-containing aqueous suspension having properties similar to ^Mucosta® ophthalmic solution UD 2% without using PVA as an additive.

As a result of diligent research to solve the above problems, the present inventors have used at least one polymer selected from the group consisting of carmellose sodium, dextran and polyvinylpyrrolidone instead of PVA. , ^Mucosta® Ophthalmic Solution UD2% has succeeded in preparing a rebamipide-containing aqueous suspension having the same properties.

That is, the present invention relates to the following.

(1) An aqueous suspension containing levamipide 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. Liquid (hereinafter, also referred to as "this aqueous suspension").

(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.

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

(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).

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

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

(9) The aqueous suspension according to any one of (1) to (8), which is administered by eye drops.

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

(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).

(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.

(13) The aqueous suspension according to any one of (1) to (12), which has a kinematic viscosity of 1.8 to 3.0 mm ² / s.

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

(15) An aqueous suspension containing 2% (w / v) of rebamipide (free form), 2% (w / v) or less of polyvinylpyrrolidone, a carboxyvinyl polymer and silver nitrate, and containing no polyvinyl alcohol. , The average particle size of rebamipide is 0.1 to 3 μm, the K value of polyvinylpyrrolidone is 30, the kinematic viscosity is 1.8 to 3.0 mm ² / s, and it is characterized by being administered by eye drops. , Aqueous suspension.

(16) The aqueous suspension according to any one of (1) to (15), which is administered by eye drops to an eye wearing soft contact lenses.

According to the present invention, it is possible to provide a rebamipide-containing aqueous suspension having the same properties as Mucosta ^{(registered trademark)} ophthalmic solution UD 2% without using PVA.

Further, according to the present invention, to provide a rebamipide-containing aqueous suspension which is expected to be less likely to cause side effects such as lacrimal duct obstruction and lacrimal pouchitis observed in the commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%". In addition, it is also possible to provide a multi-dose type rebamipide-containing aqueous suspension that can be used multiple times.

Rebamipide used in the present invention is a compound represented by the following formula.

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

The rebamipide used in the present invention can be produced according to a conventional method in the field of synthetic organic chemistry. Further, it is commercially available from SIGMA as a rebamipide hydrate.

The salt of levamipide used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and can be used with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Salt, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, horse uric acid, 1,2-ethandisulfonic acid, Isetionic 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, sulfosalicylic acid Salts with organic acids such as; quaternary ammonium salts with methyl bromide, methyl iodide, etc .; salts with halogen ions such as bromine ions, chlorine ions, iodine ions; with alkali metals such as lithium, sodium, potassium Salts; Salts with alkaline earth metals such as calcium and magnesium; Metal salts with iron, zinc, etc .; Salts with ammonia; Triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy- 1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3-propanediol, prokine, N, N-bis (phenylmethyl) -1,2-ethanediamine, etc. Examples include salts with organic amines.

In the present invention, a solvate of rebamipide such as rebamipide hydrate is included in "rebamipide or a salt thereof".

In the present invention, rebamipide (free form) is preferable as "rebamipide or a salt thereof".

In the present invention, if a geometric isomer or an optical isomer is present in rebamipide or a salt thereof, the isomer or a salt thereof is also included in the scope of the present invention. In addition, when rebamipide or a salt thereof has proton tautomerism, the tautomer or a salt thereof is also included in the scope of the present invention.

In the present invention, if polymorphs and polymorphs (crystal polymorph system) are present in levamipids or salts thereof (including hydrates or solvates), the polymorphs and polymorphs thereof. Form groups (polymorphic crystals) are also included in the scope of the present invention. Here, the crystal polymorph group (crystal polymorph system) means that the crystal shape changes depending on the conditions and conditions such as production, crystallization, and storage of those crystals (note that this state includes the formulated state). It means the individual crystal form at each stage and the whole process.

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

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

In the present invention, sodium carmellose means a cellulose derivative also also known as sodium carboxymethyl cellulose.

In the present invention, dextran means dextran having various molecular weights. Examples of the dextran contained in the present aqueous suspension include dextran 40 and dextran 70, and dextran 70 is particularly preferable.

In the present invention, polyvinylpyrrolidone means a polymer compound polymerized with N-vinyl-2-pyrrolidone. Polyvinylpyrrolidone, also called povidone, is commonly used as a thickening agent.

The K value of polyvinylpyrrolidone contained in the present aqueous suspension is preferably 17 or more, more preferably 17 to 90, further preferably 17 to 60, and most preferably 30. preferable. As will be described later, the fact that the K value is 30 is synonymous with the fact that the K value is in the range of 27 to 32.4.

Examples of the polyvinylpyrrolidone contained in this aqueous suspension include polyvinylpyrrolidone K15 (PVP K15), polyvinylpyrrolidone K17 (PVP K17), polyvinylpyrrolidone K25 (PVP K25), polyvinylpyrrolidone K30 (PVP K30), and 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), polyvinylpyrrolidone K120 (PVP K120) and the like, but polyvinylpyrrolidone K30 (PVP K30), polyvinylpyrrolidone K40 (PVP K40), polyvinylpyrrolidone K50 (PVP K50), polyvinylpyrrolidone K60 (PVP K60) are preferable. Polyvinylpyrrolidone K30 (PVP K30) is particularly preferred.

The K value of polyvinylpyrrolidone is a viscosity characteristic value that correlates with the molecular weight, and is a numerical value calculated by applying the relative viscosity value (25 ° C.) measured by a capillary viscometer to the following Fikenscher equation (1). be.

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

Here, since the K value is 90 to 108% of the displayed K value according to the description regarding the K value of the 17th revised Japanese Pharmacopoeia "Povidon", for example, "K30" is the above formula. The viscosity characteristic value (K value) calculated by applying to (1) is in the range of 27 to 32.4.

The polyvinylpyrrolidone contained in this aqueous suspension may be used alone or in any combination of two or more kinds of polyvinylpyrrolidones having different K values.

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

The safety of polyvinylpyrrolidone when it is added to ophthalmic solution at a concentration of more than 2% (w / v) has not been clinically confirmed. This does not prevent the concentration of polyvinylpyrrolidone contained in this aqueous suspension from exceeding 2% (w / v), but the concentration of polyvinylpyrrolidone contained in this aqueous suspension is It can be a reason for 2% (w / v) or less. Therefore, when the polymer contained in this aqueous suspension is polyvinylpyrrolidone in particular, the blending concentration thereof is more preferably 0.1 to 2% (w / v), and 0.5 to 0.5 to 2. It is more preferably 2% (w / v), particularly preferably 1 to 2% (w / v), and most preferably 2% (w / v).

When the concentration of polyvinylpyrrolidone contained in the aqueous suspension is 2% (w / v) or less, a carboxyvinyl polymer can be added for the purpose of improving the kinematic viscosity of the aqueous suspension.

In the present invention, the carboxyl vinyl polymer means a polymer of acrylic acid, also known as carbomer. The carboxyl vinyl polymer is commercially available. For example, CARBOPOL ^{(registered trademark)} 981NF, CARBOPOL ^{(registered trademark)} 974PNF, CARBOPOL ^{(registered trademark)} 971PNF and the like are commercially available from Lubrizol.

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). It is more preferably 0.05 to 0.3% (w / v), and most preferably 0.05 to 0.2% (w / v).

In the present invention, the 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, and 0.1 to 0.1 to. It is more preferably 3 μm, and most preferably 0.5 to 1 μm. The average particle size of rebamipide contained in this aqueous suspension is calculated by a laser diffraction method. The method for measuring the average particle size of rebamipide is also disclosed in Japanese Patent Publication No. 2010-507566 described in the section on background art.

The aqueous suspension of the present invention preferably does not contain polyvinyl alcohol (PVA). Here, "containing no polyvinyl alcohol" literally means that it does not contain polyvinyl alcohol (PVA) at all or contains substantially no polyvinyl alcohol. In addition, it is assumed that "polyvinyl alcohol" includes a partially saponified product of polyvinyl alcohol.

This aqueous suspension is administered topically to the eye in several divided doses daily for the treatment or alleviation of dry eye or its associated symptoms, but is preferably administered by eye drops once daily, four times daily. Will be done.

This aqueous suspension can be in the form of a dosage form to be administered locally to the eye, but it is preferably an eye drop filled in an eye drop container.

The kinematic viscosity of this aqueous suspension is preferably 1.0 to 10.0 mm ² / s, more preferably 1.5 to 5.0 mm ² / s, and 1.8 to 3.0 mm ² It is more preferably / s, and most preferably 2.0 to 2.5 mm ² / s. The kinematic viscosity is measured with an Ubbelohde viscometer (measurement temperature: 25.0 ° C.).

This aqueous suspension can be used as a single-use unit-dose type eye drop, or can be used as a multi-dose type eye drop by adding a preservative.

Examples of the preservative that can be added to the aqueous suspension include silver or silver salt, benzalkonium chloride, chlorobutanol and the like, but silver salt is particularly preferable.

In the present invention, the silver salt is, 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. , Protein silver and the like, but preferably means silver nitrate.

The concentration of silver or silver salt contained in this aqueous suspension is preferably more than 0.000005% (w / v), more preferably 0.000006 to 0.0002% (w / v). It is preferably 0.000007 to 0.00015% (w / v), more preferably 0.000008 to 0.00012% (w / v), and particularly preferably 0.000009 to 0.0001%. (W / v) is most preferable.

When the silver salt added to the aqueous suspension is silver nitrate, the concentration of silver nitrate contained in the aqueous suspension is preferably more than 0.00001% (w / v), 0.000011 to 0. It is more preferably .0001% (w / v), further preferably 0.000015 to 0.00005% (w / v), and even more preferably 0.00002 to 0.00005% (w / v). This is particularly preferable, and 0.00002 to 0.00004% (w / v) is most preferable.

Additives other than at least one polymer selected from the group consisting of sodium carmellose, dextran and polyvinylpyrrolidone, and preservatives can be added to the aqueous suspension. The additives include buffering agents such as sodium citrate, sodium phosphate, sodium acetate and epsilon-aminocaproic acid; isotonic agents such as sodium chloride, potassium chloride and concentrated glycerin; pH such as hydrochloric acid and sodium hydroxide. Examples include modifiers.

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.

The osmotic pressure ratio of this aqueous suspension is preferably 0.5 to 1.5, more preferably 0.7 to 1.3, and most preferably 0.9 to 1.1.

This aqueous suspension can also be applied to eyes wearing hard contact lenses and soft contact lenses.

Soft contact lenses (SCL) shall be in accordance with Pharmaceutical Tribunal No. 645, March 31, 1999, "Handling of materials to be attached when applying for manufacturing (import) approval of soft contact lenses and disinfectants for soft contact lenses". It is classified into four categories. That is, Group I (water content less than 50% and non-ionic), Group II (water content 50% or more and non-ionic), Group III (water content less than 50% and ionic). It is classified into Group IV (water content of 50% or more and ionic), and among the constituent monomers of the raw material polymer, those having an anionic molar% of 1% or more are ionic. Those with less than 1% are considered nonionic. Examples of soft contact lenses include 2-hydroxyethyl methacrylate (HEMA), (polyethylene glycol) monomethacrylate (PEGMA), glycerol methacrylate (GMA), N, N-dimethylacrylamide (DMA), and vinyl alcohol (VA). , N-vinylpyrrolidone (NVP or VP), methacrylic acid (MAA), fluorine-based methacrylate-based compound, silicon-containing methacrylate-based compound, silicone hydrogel, soft contact lenses containing cycloalkylmethacrylate and the like as main components, and the like. ..

In the present invention, "administered by eye drops to an eye wearing soft contact lenses" means that the aqueous suspension can be administered by eye drops while wearing soft contact lenses. Since it is known that benzalkonium chloride adsorbs to soft contact lenses and deforms soft contact lenses, "this aqueous suspension administered by eye drops to eyes wearing soft contact lenses" is It is preferable that benzalkonium chloride is not contained as an antiseptic.

The results of tests and pharmaceutical examples using the present aqueous suspension are shown below, but these examples are for a better understanding of the present invention and do not limit the scope of the present invention.

[Test 1]
It was investigated whether or not this aqueous suspension gels in the presence of boric acid.

(Sample preparation method)
Formulation 1-1: Sodium citrate hydrate 0.146 g, sodium chloride 0.62 g, potassium chloride 0.18 g, carboxyvinyl polymer 0.11 g, polyvinylpyrrolidone 2.0 g, silver nitrate 0.00004 g are dissolved in water and levamipide. 2.0 g was added and the mixture was stirred and suspended to adjust the pH to 6.9, and water was added to make 100 mL.

Comparative prescription 1-1: Commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%" was used.

Comparative Formula 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.

Boric acid-containing liquid: 0.5 g of boric acid, 0.4 g of sodium chloride, and 0.1 g of potassium chloride were dissolved in water to adjust the pH to 7.0, and water was added to make 100 mL.

(Test method)
0.35 mL of Formulation 1-1 was taken in a beaker, 1 mL of boric acid-containing solution was added, and the mixture was mixed. The solution was scooped up with a spatula, and those with a filamentous gel were marked as "gelled". The above operation was performed in the same manner for Comparative Prescription 1-1 and artificial tears.

(result)
The test results are shown in Table 1. No gelation was observed with Formulation 1-1 and Comparative Formulation 1-2 (artificial tears), but filamentous gelling was observed with Comparative Formulation 1-1.

(Discussion)
As described in the section on background technology, side effects such as lacrimal duct obstruction and lacrimal pouchitis are observed with Mucosta (registered ^trademark ) ophthalmic solution UD2%. The cause of this is PVA contained in Mucosta ^{(registered trademark)} ophthalmic solution UD2%. It has been pointed out that rebamipide reacts with borate ions contained in other eye drops and gels. In this test as well, it was confirmed that Mucosta ^{(registered trademark)} ophthalmic solution UD2% reacted with borate ions to gel, but this aqueous suspension did not show this effect. The suspension is expected to be less prone to side effects such as lacrimal duct obstruction and lacrimal pouchitis.

[Test 2]
Measure the particle size (D50) of rebamipide contained in the polyvinyl alcohol partially saponified product used in Mucosta ^{(registered trademark)} ophthalmic solution UD2% and the aqueous suspension in which rebamipide is suspended in each polymer other than PVA. And compared these.

(Sample preparation method)
The components shown in Table 2 are dissolved in water in a soluble concentration range between 0.5% (w / v) and 1% (w / v) to prepare each solution, which has a final concentration of 2%. An aqueous suspension was prepared by adding rebamipide in an amount (w / v).

(Test method)
The particle size distribution was measured using a laser diffraction type particle size distribution measuring device, and the particle size (D50) of rebamipide was compared.

(result)
The measurement results are shown in Table 2. When a rebamipide aqueous suspension was prepared using the polyvinyl alcohol partial saponified product used in ^Mucosta® ophthalmic solution UD 2%, the D50 of rebamipide was about 1 μm. On the other hand, when a rebamipide aqueous suspension was prepared using many polymers other than PVA, the D50 of rebamipide was on the order of tens to hundreds of μm, but carmellose sodium, dextran, and polyvinylpyrrolidone were used. In some cases, we succeeded in reducing the D50 of rebamipide to less than 3 μm.

(Discussion)
The particle size of the rebamipide aqueous suspension prepared with carmellose sodium, dextran 70 or polyvinylpyrrolidone instead of PVA was shown to be comparable to that of ^Mucosta® ophthalmic solution UD 2%. In particular, it was suggested that when polyvinylpyrrolidone K30 (povidone K30) was used instead of PVA, a particle size of rebamipide almost the same as that of ^Mucosta® ophthalmic solution UD 2% could be obtained.

[Test 3]
The polymers and concentrations at which the viscosity of the aqueous suspension could be made equivalent to "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%" were compared. In addition, the particle size distribution at that time was measured.

(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 ^{(registered trademark)} 971PNF) 0.11 g, polyvinylpyrrolidone K30 2 g, silver nitrate 0. 00003 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.

Formulations 3-2 to 3-6: Prepared in the same manner as Formulation 3-1 according to the formulation table in Table 3.

Comparative prescription: Commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%" was used.

(Test method)
The kinematic viscosity was measured using the Ubbelohde viscometer according to the "Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 1st Method". In addition, the particle size distribution of rebamipide was measured using the above-mentioned laser diffraction type particle size distribution measuring device.

(result)
The measurement results are shown in Table 3. By setting the concentration of polyvinylpyrrolidone to 6% (w / v), an aqueous suspension of rebamipide having a viscosity equivalent to that of the commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%" could be adjusted. When the concentration of polyvinylpyrrolidone is 2% (w / v) or less, the viscosity is equal to or higher than that of the commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%" by adding a carboxyl vinyl polymer. It was confirmed that the particle size of rebamipide was not affected at all while the aqueous suspension of rebamipide having the above was obtained.

(Discussion)
From the results of this test, by setting the addition concentration of polyvinylpyrrolidone to 6% (w / v) or more, rebamipide aqueous suspension having the same viscosity and particle size as the commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%". It was suggested that the solution could be prepared. On the other hand, when the concentration of polyvinylpyrrolidone added is set to 2% or less, which has been confirmed to be clinically safe, a commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2" can be added by additionally adding a carboxyl vinyl polymer. It was suggested that an aqueous suspension of rebamipide having the same viscosity and particle size as "%" could be prepared. As shown in Test 2, when the rebamipide aqueous suspension is prepared using only the carboxyl vinyl 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 the polymer had no effect on the particle size of rebamipide.

[Test 4]
The average particle size of rebamipide contained in this aqueous suspension was compared with that of "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%".

(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® ^971PNF ) 0.11 g, polyvinylpyrrolidone K30 2 g, silver nitrate 0. 00004 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.

Comparative prescription: Commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%" was used.

(Test method)
The particle size distribution was measured using a laser diffraction type particle size distribution measuring device.

(result)
The measurement results are shown in Table 4. The particle size distribution was within the range of the commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%".

(Discussion)
The particle size distribution of this aqueous suspension is within the range of commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%", and as described above, this aqueous suspension is "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%". It is considered to have the same kinematic viscosity as. Therefore, this aqueous suspension is expected to have the same therapeutic effect as "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%".

The therapeutic effect on dry eye can be evaluated by a test using a dry eye model animal or the like. It has been confirmed that this aqueous suspension has the same therapeutic effect as "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%" in a general-purpose dry eye model animal.

[Test 5]
The physicochemical stability of rebamipide contained in this aqueous suspension when stored at 60 ° C for 2 weeks and 40 ° C for 3 months was compared with that of "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%".

(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® ^971PNF ) 0.11 g, polyvinylpyrrolidone K30 2 g, silver nitrate 0. 00004 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.

Comparative prescription: Commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%" was used.

(Test method)
5 mL of Formulation 5-1 and Comparative Formulation were placed in an eye drop container and stored at 60 ° C. for 2 weeks. It was also stored at 40 ° C. for 2 and 3 months. In order to evaluate the physicochemical properties before and after storage, the following test items and measurement methods were used.

The pH, viscosity, particle size, and redispersibility (formulation 5-1 only) were measured.
-PH: The pH measurement method was carried out according to the Japanese Pharmacopoeia general test method.
-Viscosity: For the comparative formulation, the viscosity was measured using a cone plate type viscometer according to the "Japanese Bureau General Test Method Viscosity Measurement Method No. 2". For formulation 5-1 the kinematic viscosity was measured using a Ubbelohde viscometer according to the "Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 1st Method".
-Particle size: The particle size distribution was measured using a laser diffraction type particle size distribution measuring device.
-Redispersibility: The bottle was held sideways between the thumb and index finger, shaken left and right for 15 seconds, and if there was no visual adhesion to the bottle, the redispersibility was good.

(result)
The measurement results are shown in Table 5. All test items were stable with no change before and after storage. During storage, a decrease in pH was observed for the commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%", but no decrease in pH was observed for Formulation 5-1.

(Discussion)
The physicochemical stability of Formulation 5-1 was equivalent to that of the comparative formula " ^Mucosta® Ophthalmic Solution UD 2%" on the market.

[Test 6]
Commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%" is a single-use unit-dose type ophthalmic solution, but in general, a multi-dose type ophthalmic solution containing a preservative and capable of multiple instillation is preferable. For excellent convenience, we searched for preservatives that could be incorporated into 2% rebamipide-containing aqueous suspensions.

(Sample preparation method)
Comparative prescription 6-1: Commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD 2%" was used.
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 polyvinyl alcohol partial saponified product, and 0.01 g of chlorhexizing luconate are dissolved in water, and 2 g of levamipide is added. The mixture was stirred and suspended to adjust the pH to 6.0, and water was added to make 100 mL.

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

(Test method)
The storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia's storage efficacy test method. In this test, E. coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) are all used as test bacteria. Part of it was used. The content of chlorhexidine gluconate was measured by "Japanese Pharmacopoeia High Performance Liquid Chromatography".

(result)
The measurement results are shown in Tables 6 and 7. Only rebamipide-containing aqueous suspensions containing chlorobutanol or silver nitrate met the storage efficacy test.

(Discussion)
Although chlorhexidine gluconate is an excellent preservative in that it can be used for eyes wearing soft contact lenses, it has been revealed that it is not suitable as a preservative for rebamipide-containing aqueous suspensions. This is because the amount of chlorhexidine gluconate dissolved in the suspended ophthalmic solution was only about 3% with respect to the blended amount, so that a complex with rebamipide was formed and precipitated, and the preservation effect was sufficiently exhibited. It was thought that the amount did not exist.

As a result of examining various preservatives, it was suggested that silver nitrate and chlorobutanol are preservatives that can be blended in this aqueous suspension.

[Test 7]
The effect of each concentration of silver nitrate on the storage efficacy of this aqueous suspension and the stability of silver nitrate in this aqueous suspension were evaluated.

(Sample preparation method)
Formulation 7-1: Formulation 7-1 was prepared according to the formulations 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, 0.11 g of carboxyvinyl polymer (CARBOPOL ^{(registered trademark)} 971PNF), and 0. 00004 g was dissolved in water, 2 g of levamipide was added, and the mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.

Formulations 7-2-7-4: Prepared in the same manner as Formulation 7-1 according to the formulations shown in Table 8.

(Test method)
<Preservation efficacy test>
The storage efficacy test was conducted in accordance with the 17th revised Japanese Pharmacopoeia's storage efficacy test method. In this test, E. coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (Candida albicans), and Candida albicans (Candida albicans) were used as test bacteria. ..

<Stability test>
5 mL of Formulation 7-1 and Formulation 7-3 were placed in an eye drop container and stored at 40 ° C. for 3 months or at 1.2 million lux · hr with light. The content of silver nitrate in the chemical solution before and after storage was measured by "Japan-Japan inductively coupled plasma mass spectrometry".

(Test results)
The test results are shown in Tables 8 and 9. It was confirmed that this aqueous suspension containing 0.00002% (w / v) or more of silver nitrate conforms to the storage efficacy test. In addition, no change in the silver nitrate concentration in this aqueous suspension was observed during the storage period.

(Discussion)
It was shown that by adding silver nitrate as a preservative, this aqueous ophthalmic solution can be commercialized as a multi-dose type ophthalmic solution that can be instilled multiple times.

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

(Sample preparation method)
Comparative prescription: Commercially available "Mucosta ^{(registered trademark)} ophthalmic solution UD2%" was used.
Formulation 8-1: Formulation 8-1 was prepared according to the formulations 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 methyl cellulose, and 0.0000473 g of silver nitrate are dissolved in water, and 2 g of levamipide is added. The mixture was stirred and suspended to adjust the pH to 5.9, and water was added to make 100 mL.

(Test method)
A soft contact lens (2 week Accuview) was immersed in physiological saline, and the physical characteristics (diameter, base curve) were measured. The physical characteristics (diameter, base curve) when immersed in the comparative formulation or formulation 8-1 for 4 hours were measured. After the measurement, it was immersed in physiological saline for 15 minutes and the physical characteristics (diameter, base curve) were measured again. The amount of change was calculated by the following formula.
Amount of change = Measured value after immersion in chemical solution or re-immersion-Measured value during immersion in physiological saline <Unit of change amount>
mm: diameter, base curve

(Test results)
In the soft contact lenses after immersion in Formulation 8-1, a decrease in diameter and a decrease in base curve were observed, but the amount of change was equal to or less than that of the comparative formulation. In addition, the subsequent immersion in physiological saline returned the lens to the standard of contact lens for visual acuity correction (Table 13), Notification No. 349 of the Ministry of Health, Labor and Welfare.

(Discussion)
Mucosta ^{(registered trademark)} ophthalmic solution UD2% can be instilled into eyes wearing soft contact lenses. Since this aqueous suspension was within the range of 2% change in Mucosta ^{(registered trademark)} ophthalmic solution UD, it was shown that this aqueous suspension can be instilled into eyes wearing soft contact lenses.

According to the present invention, it is possible to provide a rebamipide-containing aqueous suspension having the same properties as Mucosta ^{(registered trademark)} ophthalmic solution UD 2% without using polyvinyl alcohol.

Claims (1)

The invention described in the specification.