JPH11322743A - 7-isoindoline-3-quinolinecarboxylic acid salt, its hydrate, and composition comprising the salt or hydrate as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound capable of improving the solubility at a physiologically acceptable pH, useful as a raw material for preparation, by using a compound suitable as a pyridonecarboxylic acid-based antimicrobial agent as a methanesulfonate. SOLUTION: This compound is (R)-1-cyclopropyl-8-difluoromethoxy-7-(1- methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (hereinafter T-3811) methanesulfonate. T-3811 is a well-known compound, is suspended or dissolved in an alcohol such as methanol, ethanol or the like, N,N-dimethylformamide, a methanol-ethanol mixed solvent or the like and reacted with methanesulfonic acid to give the objective compound. The T-3811 methanesulfonate is used as an active ingredient and a carrier acceptable as a preparation as is used an inert component to give a pharmaceutical formulation such as injection, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a salt of 7-isoindoline-3-quinoline carboxylic acid useful as a pyridonecarboxylic acid antibacterial agent, a hydrate thereof, and a composition containing them as an active ingredient. More specifically, (R) -1
-Cyclopropyl-8-difluoromethoxy-7- (1
-Methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate, hydrates thereof and compositions containing them as active ingredients About.

[0002]

[Prior Art] The following chemical formula

Embedded image (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1
H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (hereinafter referred to as T-3811) is a compound that is extremely excellent against Gram-positive bacteria and Gram-negative bacteria. . However, there is no known methanesulfonate, its hydrate and a composition containing them as an active ingredient and further containing an inert ingredient, specifically, for example, a carrier acceptable as a pharmaceutical.

[0003]

Since T-3811 has low solubility near neutrality, it is required to improve solubility at a physiologically acceptable pH. The purpose of the present invention is to
An object of the present invention is to enhance the solubility of -3811 and provide a composition containing T-3811 as an active ingredient, for example, various pharmaceutical preparations including injections.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, the methanesulfonate salt of T-3811 has been found to be different from the other at physiologically acceptable pH. Compared to the salt of T-3811, the solubility is remarkably higher, and the methanesulfonate hydrate of T-3811 has no crystal polymorphism and has good stability to humidity, so that the composition, especially the preparation of the formulation, The present invention was found to be extremely useful as a raw material, and the present invention was completed.

Hereinafter, the present invention will be described in detail. T-3811 of the present invention is produced, for example, by the method described in WO 97/29102.

In order to produce the methanesulfonate of T-3811, it may be produced by a generally known method for producing a salt of a compound. Specifically, the methanesulfonate of T-3811 is prepared by suspending or dissolving T-3811 in, for example, alcohols such as methanol and ethanol, N, N-dimethylformamide and a mixed solvent of methanol and ether. Can be obtained by adding methanesulfonic acid and reacting. The methanesulfonate of T-3811 is obtained by converting the methanesulfonate hydrate of T-3811 into, for example, alcohols such as methanol and ethanol, N, N-dimethylformamide and a mixed solvent of methanol and ether. It can also be produced by dehydration in a solvent. The methanesulfonate salt of T-3811 thus produced is a compound that shows the following main peaks by X-ray powder diffraction.

[0007]

[Table 1]

In order to produce T-3811 methanesulfonate hydrate, it may be produced by a generally known method for producing a salt hydrate of a compound. Specifically, for example,
T-3811 is a hydrous alcohol such as hydrous ethanol and hydrous isopropanol, hydrous acetonitrile, hydrous acetone, hydrous tetrahydrofuran, hydrous acetic acid, hydrous N,
By suspending or dissolving in N-dimethylformamide and water or the like, and adding methanesulfonic acid to react, methanesulfonic acid salt hydrate of T-3811 can be produced. The T-38 thus manufactured
The methanesulfonate hydrate of No. 11 is a compound showing the following main peaks by X-ray powder diffraction.

[0009]

[Table 2]

The inert ingredients used in the present invention include:
Pharmaceutically acceptable carriers are preferred. Specific examples include excipients such as lactose, corn starch, crystalline cellulose, mannitol, erythritol, purified sucrose; sodium carboxymethyl starch, carmellose calcium, croscarmellose sodium, Disintegrating agents such as hydroxypropylcellulose and crospovidone; and binders such as hydroxypropylcellulose, povidone and methylcellulose; magnesium stearate;
Lubricants such as calcium stearate, talc, light silicic anhydride; coating agents such as hydroxypropylmethylcellulose, ethylcellulose, polyvinyl alcohol, methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate; macrogol, glyceryl triacetate, citric acid Plasticizers such as triethyl acid; coloring agents such as iron sesquioxide, yellow iron sesquioxide, edible yellow No. 5, and titanium oxide; sweeteners such as sodium saccharin, aspartame, and reduced maltose water candy;
Viscosity agents such as gelatin and sodium alginate; tonicity agents such as mannitol, glucose, xylitol; pH modifiers such as methanesulfonic acid and sodium lactate; solvents such as water for injection; polysorbate 80, sorbitan fatty acid esters, and macrogol A surfactant such as 400;
Ointment bases such as white petrolatum, polyethylene glycol, propylene glycol, and cetanol are included.

Furthermore, crystalline cellulose or corn starch as an excipient; hydroxypropylcellulose as a binder; low-substituted hydroxypropylcellulose as a disintegrant; magnesium stearate as a lubricant; hydroxypropylmethylcellulose as a coating agent , Talc or titanium oxide; mannitol is preferred as a tonicity agent.

When a methanesulfonate of T-3811 or a hydrate thereof is used as an active ingredient and a composition with an inactive ingredient is used, a pharmaceutical composition in which the inactive ingredient is a pharmaceutically acceptable carrier is used. Is preferred. The amount of the methanesulfonate of T-3811 or its hydrate in the composition is usually 0.05 to 90% by weight, preferably 0.1 to 85% by weight of the composition. The composition of the present invention includes tablets, capsules, granules, pills, fine granules, powders or syrups for internal solids and liquids; injections, eye drops and other liquids; ointments, creams, gels , Can be formulated into dosage forms such as semisolid preparations such as jelly.

Specifically, a solid preparation for internal use is obtained by adding an active ingredient and an excipient, a binder, a disintegrant, or other appropriate additives and performing wet granulation or dry granulation to obtain a granulated product. . Granules, fine granules or powders can be prepared from the granules according to a conventional method. Further, a tablet can be obtained by adding a lubricant or the like to the granulated product and compression-molding. Tablets can also be manufactured by direct compression molding of a mixture prepared by adding an excipient, a binder, a disintegrant or other suitable additives and uniformly mixing. Both dosage forms can be coated with a suitable coating agent.

The method of administration, the dosage and the number of administrations of the composition of the present invention can be appropriately selected depending on the condition of the patient.
The dose of 1 to 100 mg / kg may be administered once or several times.

Next, the solubility of various salts of T-3811 will be described. [Test Method] The solubility of various salts of T-3811 was measured by the following method. T-3811 various salts about 50
Add 2 mL of distilled water to mg and mix and stir. Ultrasonic irradiation (SOLID STATE 1200; Ultrasonics Industry) is performed on the sample solution in cold water for 3 hours, and 0.45 μm (MILLEX-HV13; MILLIPORE)
Is filtered. The T-3811 content in the filtrate is measured by a liquid chromatography method. Table 3 shows the results.

[0016]

[Table 3]

[0017]

The present invention will now be described with reference to Examples, Reference Examples and Formulation Examples, but the present invention is not limited to these. The abbreviations have the following meanings. TFA: trifluoroacetic acid

Example 1 (R) -1-cyclopropyl-8-difluoromethoxy-
24 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was suspended in 192 mL of 50% aqueous ethanol, and the suspension was heated to 40 ° C. After heating, 5.71 g of methanesulfonic acid was added to make a homogeneous solution. Then, the mixture is stirred at the same temperature for 10 minutes, filtered, and the filtrate is concentrated.
-1-cyclopropyl-8-difluoromethoxy-7-
26.64 g of (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate hydrate is obtained. IR (KBr) cm ^-1 : ν _{C =} 1724,1615 NMR (TFA-d) δ value: 1.2-2.1 (7H, m), 3.16 (3H, s), 4.7-5.7 (4
H, m), 6.21 (1H, t, J = 72Hz), 7.5-8.0 (3H, m), 8.14 (1H, d, J = 1
0Hz), 8.78 (1H, d, J = 10Hz), 9.66 (1H, s) Moisture: 3.31% X-ray: Cu K-ALPHA1 / 40kv / 80mA

[0019]

[Table 4]

Example 2 (R) -1-cyclopropyl-8-difluoromethoxy-
0.2 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was suspended in 4 mL of ethanol and heated to 70 ° C. After that, 45 mg of methanesulfonic acid is added to make a homogeneous solution. Then, the mixture was stirred at the same temperature for 1 hour, cooled to room temperature, and the obtained precipitate was collected by filtration to give (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-
0.20 g of 2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate is obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1716,1613 NMR (TFA-d) δ value: 1.2-2.1 (7H, m), 3.16 (3H, s), 4.6-5.6 (4
H, m), 6.21 (1H, t, J = 73Hz), 7.4-8.0 (3H, m), 8.17 (1H, d, J = 1
0Hz), 8.80 (1H, d, J = 10Hz), 9.66 (1H, s) Water: 0.1% X-ray: Cu K-ALPHA1 / 40kv / 80mA

[0021]

[Table 5]

Example 3 (R) -1-cyclopropyl-8-difluoromethoxy-
0.2 g of methanesulfonic acid salt hydrate of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was added to 2 mL of ethanol. After suspending, stirring at room temperature for 15 hours, and collecting by filtration, (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-
Isoindolyl) -4-oxo-1,4-dihydro-3-
0.14 g of the methanesulfonate of quinolinecarboxylic acid is obtained. The physical properties of the compound obtained here were consistent with those obtained in Example 2. Moisture: 0.33%

Reference Example 1 (R) -1-cyclopropyl-8-difluoromethoxy-
0.5 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is suspended in 10 mL of 50% aqueous ethanol, and 50 ° C. Then, 0.14 g of phosphoric acid is added to make a homogeneous solution. Then, the mixture is stirred at the same temperature for 10 minutes and filtered. After cooling the filtrate to room temperature, the resulting precipitated crystals are collected by filtration,
(R) -1-cyclopropyl-8-difluoromethoxy-
0.32 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid phosphate are obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1722,1616 NMR (TFA-d) δ value: 1.1-2.1 (7H, m), 4.5-5.6 (4H, m), 6.20 (1
H, t, J = 75Hz), 7.4-8.0 (3H, m), 8.14 (1H, d, J = 10Hz), 8.80 (1
(H, d, J = 10Hz), 9.65 (1H, s)

Reference Example 2 (R) -1-cyclopropyl-8-difluoromethoxy-
0.7 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was suspended in 8.2 mL of 40% aqueous ethanol, and L -Add 0.16 g of lactic acid and heat to 50 ° C to make a homogeneous solution. Then, after filtration at the same temperature, the filtrate was concentrated and the resulting precipitate was collected by filtration to give (R) -1-cyclopropyl-8-
Difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-
0.57 g of L-lactate of dihydro-3-quinolinecarboxylic acid are obtained. IR (KBr) cm ^-1 : ν _{C =} 1723,1616 NMR (TFA-d) δ value: 1.2-2.1 (10H, m), 4.4-5.6 (5H, m), 6.19
(1H, t, J = 72Hz), 7.5-8.0 (3H, m), 8.14 (1H, d, J = 10Hz), 8.79
(1H, d, J = 10Hz), 9.64 (1H, s)

Reference Example 3 (R) -1-cyclopropyl-8-difluoromethoxy-
1.2 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was suspended in 9.4 mL of 25% aqueous ethanol, and 1 mol After adding 2.57 mL of / L sodium hydroxide solution, 1
A uniform solution is obtained by applying ultrasonic waves for a time. Then, the reaction solution is washed twice with chloroform, concentrated, and the resulting precipitated crystals are collected by filtration to obtain (R) -1-cyclopropyl-
8-difluoromethoxy-7- (1-methyl-2,3-
Dihydro-1H-5-isoindolyl) -4-oxo-
0.49 g of the sodium salt of 1,4-dihydro-3-quinolinecarboxylic acid is obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1636 NMR (TFA-d) δ value: 1.2-2.1 (7H, m), 4.6-5.6 (4H, m), 6.20 (1
H, t, J = 72Hz), 7.5-8.0 (3H, m), 8.17 (1H, d, J = 10Hz), 8.79 (1
(H, d, J = 10Hz), 9.66 (1H, s)

Reference Example 4 (R) -1-cyclopropyl-8-difluoromethoxy-
0.2 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was suspended in 42 mL of 50% aqueous ethanol, and citric acid was added. After adding 0.11 g, the mixture is heated to 65 ° C. to make a homogeneous solution. Then, after filtration at the same temperature, the filtrate was concentrated and the resulting precipitated crystals were collected by filtration to obtain (R) -1-cyclopropyl-8.
-Difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4
-Citrate of dihydro-3-quinolinecarboxylic acid 0.24
g is obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1724,1616

Reference Example 5 (R) -1-cyclopropyl-8-difluoromethoxy-
0.5 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is suspended in 0.75 mL of acetic acid and heated at 80 ° C. Warm to obtain a homogeneous solution. Then, after filtration at the same temperature, 2.5 mL of ethanol was added to the filtrate, and the obtained precipitated crystals were collected by filtration.
(R) -1-cyclopropyl-8-difluoromethoxy-
0.24 g of acetate of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1723,1622 NMR (TFA-d) δ value: 1.2-2.1 (7H, m), 2.28 (3H, s), 4.7-5.6 (4
H, m), 6.20 (1H, t, J = 74Hz), 7.5-8.0 (3H, m), 8.14 (1H, d, J = 1
0Hz), 8.80 (1H, d, J = 10Hz), 9.64 (1H, s)

Reference Example 6 (R) -1-cyclopropyl-8-difluoromethoxy-
1.0 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is suspended in 20 mL of 50% aqueous ethanol, and 50 ° C. Then, 0.41 mL of 6 mol / L hydrochloric acid is added to make a homogeneous solution. Then, the mixture is stirred at the same temperature for 10 minutes and filtered. After cooling the filtrate to room temperature, the resulting precipitated crystals were collected by filtration to give (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl. 0.56 g of) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride is obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1722,1616 NMR (TFA-d) δ value: 1.2-2.1 (7H, m), 4.5-5.6 (4H, m), 6.21 (1
H, t, J = 73Hz), 7.5-8.0 (3H, m), 8.15 (1H, d, J = 10Hz), 8.78 (1
(H, d, J = 10Hz), 9.65 (1H, s)

Reference Example 7 (R) -1-cyclopropyl-8-difluoromethoxy-
0.6 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was suspended in 12 mL of 20% aqueous ethanol, and magnesium ethoxy was added. After adding 74 mg of
Stir and stir for hours. Then, after cooling the reaction solution to room temperature,
The crystals were collected by filtration to give (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro. 1/2 magnesium salt of -3-quinolinecarboxylic acid
0.55 g is obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1612 NMR (TFA-d) δ value: 1.1-2.1 (7H, m), 4.5-5.6 (4H, m), 6.20 (1
H, t, J = 73Hz), 7.5-8.0 (3H, m), 8.12 (1H, d, J = 10Hz), 8.78 (1
(H, d, J = 10Hz), 9.65 (1H, s)

Reference Example 8 (R) -1-cyclopropyl-8-difluoromethoxy-
0.5 g of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is suspended in 10 mL of 50% aqueous ethanol, and 50 ° C. After heating the mixture, 0.12 g of sulfuric acid is added to make a homogeneous solution. Then, the mixture is stirred at the same temperature for 10 minutes and filtered. After cooling the filtrate to room temperature, the resulting precipitated crystals are collected by filtration to obtain (R)
-1-cyclopropyl-8-difluoromethoxy-7-
0.34 g of the sulfate of (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is obtained. IR (KBr) cm ^-1 : ν _{C = 0} 1724,1615 NMR (TFA-d) δ value: 1.2-2.1 (7H, m), 4.6-5.6 (4H, m), 6.20 (1
H, t, J = 73Hz), 7.5-8.0 (3H, m), 8.12 (1H, d, J = 10Hz), 8.80 (1
(H, d, J = 10Hz), 9.65 (1H, s)

Formulation Example 1 (R) -1-cyclopropyl-8-difluoromethoxy-
380.4 g of methanesulfonate hydrate of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 83.1 g of lactose , Corn starch 36g and carboxymethyl starch sodium (Primogel; Matsutani Kagaku) 27g are mixed, then put into a kneading machine (small tabletop kneader: Koike Iron Works), and 6% hydroxypropylcellulose (HPC-L; Nippon Soda) aqueous solution Knead while gradually adding 180 g. The kneaded material is sized with a power mill (PS-04S: Dalton; 2 mm herringbone screen), and dried by blowing air at 40 ° C overnight. After drying and sizing with a power mill (20 mesh square screen), 2.7 g of magnesium stearate is added and mixed to obtain a tableting powder. One tablet weighs 180 mg using a rotary tableting machine (HP-18; Hata Tekko) using a 7.5 mm diameter punch.
And (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,
A tablet is obtained containing 100 mg of (3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (as free base). These tablets are coated with an aqueous film according to a conventional method (per tablet; hydroxypropyl methylcellulose (TC-5; Shin-Etsu Chemical) 4 mg, Macrogol 6000 0.8 mg, titanium oxide 0.4 m)
g, talc 0.4 mg) to give a film-coated tablet.

Formulation Example 2 (R) -1-cyclopropyl-8-difluoromethoxy-
380.4 g of methanesulfonic acid salt hydrate of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, crystalline cellulose ( After mixing 70.2 g of Avicel PH101 (Asahi Kasei) and 30 g of corn starch, the mixture was charged into a fluidized bed granulator (Multiplex: MP-01; Powrex) and 270 g of a 1% aqueous solution of hydroxypropylcellulose (HPC-L; Nippon Soda) was gradually added. And granulate. Further, an appropriate amount of water is sprayed, and after drying, particles having good flowability are obtained. 54 g of low-substituted hydroxypropylcellulose (L-HPC LH11; Shin-Etsu Chemical) and 2.7 g of magnesium stearate are added and mixed to obtain a powder for tableting. This powder was tableted with a rotary tableting machine (HP-18) using a 7.5 mm diameter punch so that the weight of one tablet was 180 mg.
(R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-
5-isoindolyl) -4-oxo-1,4-dihydro-
A tablet is obtained containing 100 mg of 3-quinolinecarboxylic acid (as free base). The tablets are coated with an aqueous film according to a conventional method (per tablet; hydroxypropylmethylcellulose (TC-5) 4 mg, titanium oxide 0.4 mg, talc 0.
4 mg) to give a film-coated tablet.

Formulation Example 3 (R) -1-cyclopropyl-8-difluoromethoxy-
253.6 g of methanesulfonic acid salt hydrate of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, crystalline cellulose ( Avicel PH101) 46.8g, corn starch
20 g and 1.8 g of hydroxypropylcellulose (HPC-L) were mixed, compression-granulated, and milled (Comil: QC-197S; QUADR
O-Powrex), and 36 g of low-substituted hydroxypropylcellulose (L-HPC LH11) and 1.8 g of magnesium stearate are added and mixed to obtain a tableting powder. This powder is tableted with a rotary tableting machine (HP-18) using a 7.5 mm diameter punch so that the weight of each tablet is 180 mg.
(R) -1-cyclopropyl-8-difluoromethoxy-
A tablet is obtained containing 100 mg of 7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (as free base). The tablets are coated with a film in an aqueous system (per tablet; hydroxypropylmethylcellulose (TC-5) 4 mg, titanium oxide 0.8 mg, talc 0.4 mg) according to a conventional method to obtain film-coated tablets.

Formulation Example 4 (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3) was stirred with 958 g of water for injection.
-Dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate hydrate (6.338 g) is added and dissolved. 0.1 mol / L methanesulfonic acid 0.62 mL, D-mannitol 5
Add 0 g and stir further. After complete dissolution, filtration is performed with a 0.22 μm membrane filter. 100 mL of this filtrate
After dispensing into vials, sealing with rubber stoppers and aluminum caps, steam sterilization (121 ° C. for 20 minutes) was performed, and (R) -1-cyclopropyl-8-difluoromethoxy-7- ( An injection is obtained which contains 500 mg of 1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (as free base).

[0035]

The methanesulfonate of T-3811 is
At physiologically acceptable pH, the solubility is remarkably high, and furthermore, methanesulfonate of T-3811.
The hydrate has no crystal polymorphism and has good stability to humidity. Therefore, a composition containing T-3811 as an active ingredient, particularly
Useful as a raw material for -3811 preparations.

Claims (4)

[Claims] (1) (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-
1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate. (2) (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-
1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate hydrate. (3) (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-
1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate or (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2 , 3-dihydro-1H-
5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate hydrate comprising any active ingredient and an inactive ingredient. 4. The composition according to claim 3, wherein the inert ingredient is a pharmaceutically acceptable carrier.