Freeze-dried preparation containing cephalosporins having a catechol group and method for producing the same

Abstract

The present invention pertains to a lyophilized formulation, and a method for producing a lyophilized formulation, wherein the lyophilized formulation contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the water content is controlled, and the repreparation time is reduced.　According to a method for producing a lyophilized formulation, the method comprising at least the following steps: 1) a step for cooling a liquid containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a lyophilization chamber to a predetermined cooling temperature; and 2) a step for spraying mist into the chamber, the water content can be 0.5% or less and the repreparation time can be 30 seconds or less, when the lyophilized formulation has a specific surface area of 0.6-1.1 m2 / g.

Description

[Technical Field]

[0001] The preparation of the present invention is a freeze-dried preparation containing a cephalosporin compound that has a broad antibacterial spectrum and exhibits particularly strong antibacterial activity against β-lactamase-producing Gram-negative bacteria, and the moisture content in the preparation is below the moisture content at which the active ingredient does not decompose, and the reconstitution time is short. [Background technology]

[0002] Various β-lactam drugs have been developed to date, and β-lactam drugs have become clinically very important antibacterial drugs. However, an increasing number of bacterial species have acquired resistance to β-lactam drugs by producing β-lactamase, which degrades β-lactam drugs. To solve this problem, a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof has been discovered, which exhibits a strong antibacterial spectrum against various bacteria, including gram-negative and / or gram-positive bacteria (Patent Document 1). Formula (I): [ka]

[0003] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used as a freeze-dried injection. A freeze-dried preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is disclosed in Patent Document 2.

[0004] The manufacturing process for freeze-dried formulations includes: (1) a pre-freezing process in which liquid materials to be dried (e.g., drugs filled in vials, aqueous solutions containing additives) stored in a drying chamber are frozen and solidified; (2) a primary drying process in which moisture is removed from the materials to be dried that have been frozen in the pre-freezing process; and (3) a secondary drying process in which trace amounts of unfrozen water contained in the materials to be dried that have become dry solids after the primary drying process are removed and the materials to be dried are dried until they reach a predetermined moisture content.

[0005] During the freeze-drying process, the material to be dried in each vial is supercooled in the preliminary freezing step (1), and then ice nuclei are formed.Then, in the primary drying step (2), the frozen ice nuclei are sublimated, and in the secondary drying step (3), the unfrozen unfrozen water and bound water are removed.

[0006] "Supercooling" during the pre-freezing process refers to a state in which a substance remains in a state of phase change even when the temperature is below the temperature at which it should change. For example, it is a phenomenon in which a liquid does not solidify even when cooled past its freezing point, but remains in a liquid state. In the case of water, this refers to a state in which the substance does not freeze even at temperatures below zero degrees Celsius, which is a metastable state, but if it is subjected to an impact in a supercooled state, it will freeze rapidly.

[0007] When the temperature is supercooled to a very low level, freezing begins and ice nuclei are formed, but the particle size of the formed ice nuclei is small. The ice nuclei are sublimated during the primary drying process, and the ice nuclei become pores, i.e., pores, in the freeze-dried formulation. Therefore, if the particle size of the ice nuclei is small, the pore size of the freeze-dried formulation will also be small, and even if the freeze-dried formulation is placed in water, the water penetration rate into the formulation will be slow and the reconstitution time will be long.

[0008] Recently, to overcome uneven ice nucleation and crystal growth of the material to be dried in the pre-freezing process, To achieve this, various nucleation control technologies have been developed. To control ice nucleation, the product temperature is cooled to below 0°C, and then an ice fog made from chilled nitrogen gas and water vapor (pure steam) is formed. This ice fog is then sprayed into the freeze-drying chamber to promote nucleation in the solution, resulting in rapid ice nucleation in all vials.

[0009] When the supercooling state ends, freezing begins, and ice nuclei are formed at a relatively high temperature, the particle size of the formed ice nuclei becomes larger than that of ice nuclei that remain supercooled down to a very low temperature. Therefore, if the particle size of the ice nuclei is large, the pore size of the freeze-dried preparation also becomes large. Therefore, when the freeze-dried preparation is placed in water, the water permeates the preparation at a high rate, and the reconstitution time is short.

[0010] Non-Patent Document 1 describes that spraying ice fog makes it possible to control the freezing temperature, and that the pore size is larger than that of a normally frozen product, which is expected to shorten the primary drying time. However, this document does not describe or suggest shortening the reconstitution time of a freeze-dried preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or reducing the moisture content of the freeze-dried preparation.

[0011] Patent Document 3 discloses a freeze-drying method that uses ice fog to form uniform ice nuclei. However, this document neither describes nor suggests shortening the reconstitution time of a freeze-dried formulation or reducing the moisture content of a freeze-dried formulation. Furthermore, this document neither describes nor suggests shortening the reconstitution time of a freeze-dried formulation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or reducing the moisture content of a freeze-dried formulation. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Journal of Pharmaceutical Machinery and Technology, Vol. 90, No. 2, pp. 39-51 (2015) [Patent documents]

[0013] [Patent Document 1] International Publication No. 2010 / 050468 [Patent Document 2] International Publication No. 2016 / 035846 [Patent Document 3] Special Publication No. 2014-512510 Summary of the Invention [Problem to be solved by the invention]

[0014] The freeze-dried formulation disclosed in Patent Document 2 takes a long time to dissolve in water (hereinafter, sometimes referred to as the "reconstitution time"), and preparation of an aqueous solution for injection takes a long time. Furthermore, depending on the moisture content in the formulation, there is a risk that the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may decompose. Therefore, there has been a need for a freeze-dried formulation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which has a short reconstitution time and in which the moisture content in the formulation is kept below a certain moisture content, thereby suppressing decomposition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0015] As a result of extensive investigations, the present inventors have found that a method for producing a freeze-dried formulation comprising: 1) a step of cooling a liquid containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber at a predetermined cooling temperature, particularly at −30° C. to −5° C.; and 2) a step of spraying a mist into the chamber (hereinafter sometimes referred to as the “production method of the present invention”) can produce a freeze-dried formulation having a specific surface area of ​​0.6 to 1.1 m. 2 / g, shortening the reconstitution time of the freeze-dried preparation, and further, controlling the water content can suppress decomposition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Furthermore, it has been found that the specific surface area of ​​a freeze-dried preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be reduced to 0.6 to 1.1 m. 2 / g, it has been found that the reconstitution time of the freeze-dried formulation can be shortened, and further, by controlling the water content, it is possible to suppress the decomposition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof (hereinafter, the formulation of the present invention may be referred to as the "preparation of the present invention").

[0016] That is, the present invention is (1) Formula (I): [ka] or a pharmaceutically acceptable salt thereof, the method for producing a freeze-dried preparation comprising at least the following steps: Step 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber to a predetermined cooling temperature; and Step 2) spraying mist into the chamber; (2) A method for producing a freeze-dried formulation, comprising the following steps after step 2): Step 3) further cooling; Step 4) maintaining the temperature at or above the glass transition temperature; and, Step 5) drying step; (3) The liquid contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols The method for producing a freeze-dried preparation according to (1) or (2) above, wherein the freeze-dried preparation is a liquid containing (4) The liquid contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) sodium chloride, and, c) sucrose The method for producing a freeze-dried preparation according to (1) or (2) above, wherein the freeze-dried preparation is a liquid containing (5) The method for producing a freeze-dried preparation according to any one of (1) to (4) above, wherein step 1) is a step of cooling to −30° C. to −5° C. (6) The method for producing a freeze-dried preparation according to any one of (1) to (4) above, wherein step 1) is a step of cooling to −22° C. to −10° C. (7) The method for producing a freeze-dried preparation according to any one of (1) to (6) above, wherein step 2) is a step of spraying ice mist. (8) The method for producing a freeze-dried preparation according to any one of (2) to (7) above, wherein step 5) is a primary drying step and a secondary drying step. (9) The method for producing a freeze-dried preparation according to (8) above, wherein the time for the primary drying step in step 5) is 100 hours or less. (10) A freeze-dried preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, produced by the production method according to any one of (1) to (9) above. (11) The specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m 2 / g of the freeze-dried preparation according to (10). (12) Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m 2 / g of a lyophilized formulation; (13) The standard deviation of the specific surface area of ​​the freeze-dried preparation is 0.2 m 2 / g or less, (14) The freeze-dried preparation according to any one of (11) to (13) above, wherein the reconstitution time of the freeze-dried preparation is within 30 seconds. (15) The freeze-dried preparation according to any one of (11) to (14) above, wherein the water content of the freeze-dried preparation is 0.5% or less. (16) The compound of formula (I) or a pharmaceutically acceptable salt thereof Formula (II): [ka] A method for producing a freeze-dried preparation according to any one of (1) to (9) above, wherein the freeze-dried preparation is an amorphous sodium salt of (17) The freeze-dried preparation according to any one of (10) to (15) above, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is an amorphous sodium salt represented by formula (II). Regarding. [Effects of the Invention]

[0017] The method of the present invention is used to prepare a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the compound has a specific surface area of ​​0.6 to 1.1 m. 2 It was possible to produce a freeze-dried preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and having a specific surface area of ​​0.6 to 1.1 m / g. 2 By preparing a freeze-dried formulation with a water content of 0.5% or less, the reconstitution time could be shortened and the water content could be kept below 0.5%. By controlling the water content at this level, the decomposition of the compound of formula (I) or a pharmaceutically acceptable salt thereof could be suppressed. [Brief explanation of the drawings]

[0018] [Figure 1] Relationship between the specific surface area (m2 / g) of a freeze-dried preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and the moisture content (%) of the freeze-dried preparation BEST MODE FOR CARRYING OUT THE INVENTION

[0019] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprising" is meant to be open-ended and not to exclude unlisted elements. The present invention will be described below with reference to embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. It should also be understood that the terms used herein are used in the same sense as commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of any conflict, the present specification (including definitions) shall prevail.

[0020] The active ingredient used in the process of the present invention is herein represented by formula (I): [ka] which is essentially represented by formula (I'): [ka] The sodium salt represented by formula (I) can also take the form: [ka] and [ka] Includes.

[0021] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II) may be amorphous (non-crystalline). The molecular weight of the compound represented by formula (I) is 752.21, and the molecular weight of the sodium salt represented by formula (II) is 774.20. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II) may be produced by the production methods described in WO 2010 / 050468, WO 2016 / 035845, and WO 2016 / 035847.

[0022] The formulation of the present invention contains one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides and magnesium chloride, as well as a sugar and / or a sugar alcohol, in order to stabilize the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II).

[0023] The alkali metal chloride that can be used is one that stabilizes the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II), and is listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals, Pharmaceutical Additives Standards, and the Official Specification of Food Additives. Specific examples include sodium chloride, lithium chloride, potassium chloride, etc., and sodium chloride is preferred.

[0024] The alkaline earth metal chloride may be one that stabilizes the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II), and is listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Pharmacopoeial Pharmaceutical Standards, the Pharmaceutical Additives Standards, and the Official Specification of Food Additives. Specific examples include barium chloride and calcium chloride, and calcium chloride is preferred.

[0025] The transition metal chloride that can be used is one that stabilizes the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II), and is listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals Other Than the Japanese Pharmacopoeia, the Pharmaceutical Additives Standards, and the Official Specification of Food Additives. Specific examples include chromium chloride and zinc chloride, and zinc chloride is preferred.

[0026] In addition, magnesium chloride may be contained to stabilize the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II). As the magnesium chloride, magnesium chloride listed in the Japanese Pharmacopoeia, the Standards for Pharmaceuticals Other Than the Japanese Pharmacopoeia, the Standards for Pharmaceutical Additives, and the Official Specification of Food Additives can be used.

[0027] The sugar and / or sugar alcohol may be one that stabilizes the compound represented by formula (I) or its pharmaceutically acceptable salt, and the sodium salt represented by formula (II) and is listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia's Non-Drug Standards, the Pharmaceutical Additives Standards, and the Official Specification of Food Additives. Specifically, the sugar may be a monosaccharide, disaccharide, or polysaccharide, and preferably, the monosaccharide may be glucose or fructose, the disaccharide may be lactose, sucrose (white sugar, refined white sugar), trehalose, maltose, or isomaltose, the polysaccharide may be starch or dextrin, and the sugar alcohol may be xylitol, sorbitol, mannitol, lactitol, or the like, and more preferably, sucrose (white sugar, refined white sugar).

[0028] Furthermore, in order to stabilize the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II), an alkali metal salt, alkaline earth metal salt, transition metal salt, or magnesium salt of an organic acid or an inorganic acid, or a hydrate thereof may be contained.

[0029] Specific examples of the organic acid or inorganic acid include p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, hydrochloric acid, and hydrobromic acid, and preferably p-toluenesulfonic acid and sulfuric acid.

[0030] Specific examples of the alkali metal salts, alkaline earth metal salts, transition metal salts, or magnesium salts of the organic or inorganic acids, or hydrates thereof, include sodium salts, lithium salts, potassium salts, calcium salts, zinc salts, and magnesium salts, with sodium salts and magnesium salts being preferred, and sodium salts being more preferred. Specific and more preferred salts include sodium p-toluenesulfonate, magnesium p-toluenesulfonate, sodium sulfate, and magnesium sulfate. Specific and particularly preferred salts are sodium p-toluenesulfonate and sodium sulfate.

[0031] Representative examples of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof include the following. [ka]

[0032] In addition to the additives described above, antioxidants, buffers, soothing agents, preservatives, etc. that stabilize the compound represented by formula (I) or its pharmaceutically acceptable salt, and the sodium salt represented by formula (II), and that are listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Drug Standards, the Pharmaceutical Additives Standards, and the Official Specification of Food Additives and are suitable for injections, may be added. Specific examples of antioxidants include sodium bisulfite, sodium metabisulfite, and ascorbic acid. Buffers include citrate, acetate, and phosphate. Soothing agents include procaine hydrochloride, lidocaine hydrochloride, chlorobutanol, and benzyl alcohol. Preservatives include methyl parahydroxybenzoate, propyl parahydroxybenzoate, phenol, cresol, benzyl alcohol, chlorobutanol, and chlorocresol.

[0033] The combination of one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride, and a sugar and / or a sugar alcohol that can stabilize the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II) can be used. The specific combinations are: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, b) sodium salt of formula (II), sodium chloride, sucrose; c) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, d) Sodium salt of formula (II), magnesium chloride, sucrose. Preferably, a) or b) is used, and more preferably b).

[0034] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof contains sodium chloride as the alkali metal chloride and sucrose as the sugar or sugar alcohol, the contents are 0.7 to 5.0 molar equivalents of sodium chloride and 0.3 to 4.0 molar equivalents of sucrose, preferably 1.25 to 4.5 molar equivalents of sodium chloride and 0.75 to 3.5 molar equivalents of sucrose, and more preferably 1.5 to 4.0 molar equivalents of sodium chloride and 1.0 to 3.0 molar equivalents of sucrose.

[0035] When the sodium salt represented by formula (II) contains sodium chloride as the alkali metal chloride and sucrose as the sugar or sugar alcohol, the contents are 0.7 to 5.0 molar equivalents of sodium chloride and 0.3 to 4.0 molar equivalents of sucrose, preferably 1.25 to 4.5 molar equivalents of sodium chloride and 0.75 to 3.5 molar equivalents of sucrose, and more preferably 1.5 to 4.0 molar equivalents of sodium chloride and 1.0 to 3.0 molar equivalents of sucrose.

[0036] Combinations of one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides and magnesium chloride, sugars and / or sugar alcohols, and alkali metal salts, alkaline earth metal salts, transition metal salts or magnesium salts of organic or inorganic acids or hydrates thereof that can stabilize the compound represented by formula (I) or a pharmaceutically acceptable acid addition salt thereof or a solvate thereof, and the sodium salt represented by formula (II) can be used. The specific combinations are: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, an alkali metal salt of p-toluenesulfonic acid, b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, an alkali metal salt of sulfate; c) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, an alkali metal salt of p-toluenesulfonic acid, an alkali metal salt of sulfuric acid, d) sodium salt of formula (II), sodium chloride, sucrose, alkali metal salt of p-toluenesulfonic acid; e) sodium salts of formula (II), sodium chloride, sucrose, alkali metal salts of sulfate, f) sodium salt of formula (II), sodium chloride, sucrose, alkali metal salts of p-toluenesulfonic acid, alkali metal salts of sulfuric acid, g) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, an alkali metal salt of p-toluenesulfonic acid, h) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, an alkali metal salt of sulfate; i) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, an alkali metal salt of p-toluenesulfonic acid, or an alkali metal salt of sulfuric acid; j) sodium salt of formula (II), magnesium chloride, sucrose, alkali metal salt of p-toluenesulfonic acid; k) sodium salt of formula (II), magnesium chloride, sucrose, alkali metal salts of sulfate, l) Sodium salts represented by formula (II), magnesium chloride, sucrose, alkali metal salts of p-toluenesulfonic acid, and alkali metal salts of sulfate. Preferably, it is c) or f), more preferably f).

[0037] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof contains sodium chloride as an alkali metal chloride, sucrose as a sugar or sugar alcohol, an alkali metal salt of p-toluenesulfonic acid, and an alkali metal salt of sulfuric acid, the contents thereof are 0.7 to 5.0 molar equivalents of sodium chloride, 0.3 to 4.0 molar equivalents of sucrose, 0.25 to 2.5 molar equivalents of an alkali metal salt of p-toluenesulfonic acid, and 0.05 to 2.0 molar equivalents of an alkali metal salt of sulfuric acid. The amounts are preferably 1.25 to 4.5 molar equivalents of sodium chloride, 0.5 to 4 molar equivalents of sucrose, 0.5 to 2.25 molar equivalents of the alkali metal salt of p-toluenesulfonate, and 0.075 to 1.5 molar equivalents of the alkali metal salt of sulfuric acid, and more preferably 1.5 to 4.0 molar equivalents of sodium chloride, 1.0 to 3.0 molar equivalents of sucrose, 0.75 to 2.0 molar equivalents of the alkali metal salt of p-toluenesulfonate, and 0.1 to 1.0 molar equivalents of the alkali metal salt of sulfuric acid.

[0038] When sodium chloride as an alkali metal chloride, sucrose as a sugar or sugar alcohol, an alkali metal salt of p-toluenesulfonic acid, and an alkali metal salt of sulfuric acid are contained relative to the sodium salt represented by formula (II), the contents thereof are preferably 0.7 to 5.0 molar equivalents of sodium chloride, 0.3 to 4.0 molar equivalents of sucrose, 0.25 to 2.5 molar equivalents of the alkali metal salt of p-toluenesulfonic acid, and 0.05 to 2.0 molar equivalents of the alkali metal salt of sulfuric acid. Preferably, the amount is 1.25 to 4.5 molar equivalents of sodium chloride, 0.5 to 4.0 molar equivalents of sucrose, 0.5 to 2.25 molar equivalents of an alkali metal salt of p-toluenesulfonic acid, and 0.075 to 1.5 molar equivalents of an alkali metal salt of sulfuric acid, and more preferably 1.5 to 4.0 molar equivalents of sodium chloride, 1.0 to 3.0 molar equivalents of sucrose, 0.75 to 2.0 molar equivalents of an alkali metal salt of p-toluenesulfonic acid, and 0.1 to 1.0 molar equivalent of an alkali metal salt of sulfuric acid.

[0039] Combinations of one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides and magnesium chloride, sugars and / or sugar alcohols, and alkali metal salts, alkaline earth metal salts, transition metal salts or magnesium salts of organic or inorganic acids or hydrates thereof that can stabilize the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the sodium salt represented by formula (II) can be used. The specific combinations are: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, sodium p-toluenesulfonate; b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, sodium sulfate, c) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate, d) sodium salt of formula (II), sodium chloride, sucrose, sodium p-toluenesulfonate; e) sodium salt of formula (II), sodium chloride, sucrose, sodium sulfate, f) sodium salt of formula (II), sodium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate, g) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, sodium p-toluenesulfonate; h) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, sodium sulfate, i) a compound of formula (I) or a pharmaceutically acceptable acid thereof, magnesium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate, j) sodium salt of formula (II), magnesium chloride, sucrose, sodium p-toluenesulfonate; k) sodium salt of formula (II), magnesium chloride, sucrose, sodium sulfate, l) Sodium salt of formula (II), magnesium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate. Preferably, it is c) or f), more preferably f).

[0040] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof contains sodium chloride as an alkali metal chloride, sucrose as a sugar or sugar alcohol, sodium p-toluenesulfonate as an alkali metal salt of p-toluenesulfonic acid, and sodium sulfate as an alkali metal salt of sulfuric acid, the contents thereof are 0.7 to 5.0 molar equivalents of sodium chloride, 0.3 to 4.0 molar equivalents of sucrose, 0.25 to 2.5 molar equivalents of sodium p-toluenesulfonate, and 0.7 to 5.0 molar equivalents of sulfuric acid. The amount of sodium is 0.05 to 2.0 molar equivalents, preferably 1.25 to 4.5 molar equivalents of sodium chloride, 0.5 to 4.0 molar equivalents of sucrose, 0.5 to 2.25 molar equivalents of sodium p-toluenesulfonate, and 0.075 to 1.5 molar equivalents of sodium sulfate, and more preferably 1.5 to 4.0 molar equivalents of sodium chloride, 1.0 to 3.0 molar equivalents of sucrose, 0.75 to 2.0 molar equivalents of sodium p-toluenesulfonate, and 0.1 to 1.0 molar equivalent of sodium sulfate.

[0041] When the sodium salt represented by formula (II) contains sodium chloride as the alkali metal chloride, sucrose, sodium p-toluenesulfonate, and sodium sulfate as the sugar or sugar alcohol, the contents are 0.7 to 5.0 molar equivalents of sodium chloride, 0.3 to 4.0 molar equivalents of sucrose, 0.25 to 2.5 molar equivalents of sodium p-toluenesulfonate, and 0.05 to 2.0 molar equivalents of sodium sulfate, preferably 1.25 to 4.5 molar equivalents of sodium chloride, 0.5 to 4.0 molar equivalents of sucrose, 0.5 to 2.25 molar equivalents of sodium p-toluenesulfonate, and 0.075 to 1.5 molar equivalents of sodium sulfate, and more preferably 1.5 to 4.0 molar equivalents of sodium chloride, 1.0 to 3.0 molar equivalents of sucrose, 0.75 to 2.0 molar equivalents of sodium p-toluenesulfonate, and 0.1 to 1.0 molar equivalent of sodium sulfate.

[0042] Furthermore, sodium gluconate may be contained as an additive.

[0043] Combinations of one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides and magnesium chloride, sugars and / or sugar alcohols, alkali metal salts, alkaline earth metal salts, transition metal salts or magnesium salts of organic or inorganic acids or hydrates thereof, and sodium gluconate that can stabilize the compound represented by formula (I) or its pharmaceutically acceptable acid addition salt or solvate thereof, and the sodium salt represented by formula (II) can be used. Specific combinations include: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, sodium p-toluenesulfonate, sodium gluconate, b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, sodium sulfate, sodium gluconate, c) a compound of formula (I) or a pharmaceutically acceptable salt thereof, sodium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate, sodium gluconate, d) sodium salt of formula (II), sodium chloride, sucrose, sodium p-toluenesulfonate, sodium gluconate, e) sodium salts of formula (II), sodium chloride, sucrose, sodium sulfate, sodium gluconate, f) sodium salt of formula (II), sodium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate, sodium gluconate, g) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, sodium p-toluenesulfonate, sodium gluconate, h) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, sodium sulfate, sodium gluconate, i) a compound of formula (I) or a pharmaceutically acceptable salt thereof, magnesium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate, sodium gluconate, j) sodium salt of formula (II), magnesium chloride, sucrose, sodium p-toluenesulfonate, sodium gluconate; k) sodium salt of formula (II), magnesium chloride, sucrose, sodium sulfate, sodium gluconate, l) Sodium salt of formula (II), magnesium chloride, sucrose, sodium p-toluenesulfonate, sodium sulfate, sodium gluconate. Preferably, it is c) or f), more preferably f).

[0044] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof contains sodium chloride as an alkali metal chloride, sucrose as a sugar or sugar alcohol, sodium p-toluenesulfonate as an alkali metal salt of p-toluenesulfonic acid, and sodium sulfate as an alkali metal salt of sulfuric acid, the contents thereof are 0.7 to 5.0 molar equivalents of sodium chloride, 0.3 to 4.0 molar equivalents of sucrose, 0.25 to 2.5 molar equivalents of sodium p-toluenesulfonate, 0.05 to 2.0 molar equivalents of sodium sulfate, and 0.05 to 1.0 molar equivalents of sodium gluconate. 0.0 molar equivalents, preferably 1.25 to 4.5 molar equivalents of sodium chloride, 0.5 to 4.0 molar equivalents of sucrose, 0.5 to 2.25 molar equivalents of sodium p-toluenesulfonate, 0.075 to 1.5 molar equivalents of sodium sulfate, and 0.075 to 0.75 molar equivalents of sodium gluconate, more preferably 1.5 to 4.0 molar equivalents of sodium chloride, 1.0 to 3.0 molar equivalents of sucrose, 0.75 to 2.0 molar equivalents of sodium p-toluenesulfonate, 0.1 to 1.0 molar equivalents of sodium sulfate, and 0.1 to 0.5 molar equivalents of sodium gluconate.

[0045] When sodium chloride as an alkali metal chloride, sucrose, sodium p-toluenesulfonate, and sodium sulfate as sugars or sugar alcohols are contained in the sodium salt represented by formula (II), the contents thereof are 0.7 to 5.0 molar equivalents of sodium chloride, 0.3 to 4.0 molar equivalents of sucrose, 0.25 to 2.5 molar equivalents of sodium p-toluenesulfonate, 0.05 to 2.0 molar equivalents of sodium sulfate, and 0.05 to 1.0 molar equivalents of sodium gluconate, preferably 1.2 molar equivalents of sodium chloride. 5 to 4.5 molar equivalents of sodium chloride, 0.5 to 4.0 molar equivalents of sucrose, 0.5 to 2.25 molar equivalents of sodium p-toluenesulfonate, 0.075 to 1.5 molar equivalents of sodium sulfate, and 0.075 to 0.75 molar equivalents of sodium gluconate, more preferably 1.5 to 4.0 molar equivalents of sodium chloride, 1.0 to 3.0 molar equivalents of sucrose, 0.75 to 2.0 molar equivalents of sodium p-toluenesulfonate, 0.1 to 1.0 molar equivalents of sodium sulfate, and 0.1 to 0.5 molar equivalents of sodium gluconate.

[0046] The formulation of the present invention is prepared by dissolving or suspending the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the sodium salt represented by formula (II), and additives in water, followed by drying. The drying method may be any method that ensures stability of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the sodium salt represented by formula (II), but freeze-drying is preferred.

[0047] The freeze-drying method mainly consists of two steps: 1) freezing the sample, and 2) drying the frozen solid.

[0048] The freeze-drying method can be further divided into 1) pre-freezing and drying steps, 2) primary drying, and 3) secondary drying.

[0049] Prefreezing is the process of freezing a sample beforehand. The water in the sample is not pure water but something dissolved in it, so it will not freeze at 0°C. Strictly speaking, it is necessary to measure the eutectic point (the temperature at which the sample freezes) and ensure that the sample is frozen below that temperature. Liquids containing the compound represented by formula (I) or its pharmaceutically acceptable salt and additives will often not freeze unless the freezing temperature is set to approximately -40°C or below. After freezing, ice crystals will form.

[0050] Primary drying is the process of sublimating a frozen sample under vacuum. In primary drying, the water (ice) in the sample sublimates gradually from the surface of the sample, so it takes time for all the ice to sublime. Sublimation means that a solid becomes a gas directly without passing through a liquid state, or a gas becomes a solid directly. In the case of freeze-drying, ice crystals become water vapor directly without passing through water.

[0051] Although most of the water can be removed in the primary drying stage, the water bonded between molecules (bound water) still remains. To remove this bound water, the sample is heated to a temperature that does not affect it, a process called secondary drying.

[0052] This freeze-drying method is carried out using a freeze-dryer. A vacuum freeze-dryer consisting of at least a sample drying section and a vapor trap section (cold trap section) can be used as the freeze-dryer, and the pressure during vacuum drying is reduced using a vacuum pump.

[0053] The heat source for freeze dryers is required to freeze samples in advance (pre-freezing), and in the case of large shelf-type devices, the shelves are directly cooled by pipes or by circulating a low-temperature heat transfer medium. In the case of laboratory-type devices, samples are pre-frozen using a low-temperature water bath or freezer.

[0054] The heat source of a freeze dryer for warming samples is intended to promote sublimation during the drying process and remove bound moisture, and shelf-type freeze dryers are designed to circulate a heater or heated heat medium directly on the shelves. In laboratory-type freeze dryers, when freeze-drying samples in flasks, room temperature is the heat source.

[0055] The vacuum pump sucks air out of the freeze dryer, lowering the pressure in the entire freeze dryer and maintaining a vacuum. Maintaining a vacuum also serves to self-freeze the sublimation surface of the sample.

[0056] In freeze-drying, to promote drying, it is necessary to constantly remove the moisture generated from the sample and reduce the humidity of the environment in which the sample is placed. However, substances have a saturated humidity level, and if the environmental humidity becomes too high, evaporation of the moisture is suppressed and drying stops. In this case, the cold trap functions to exhaust the water vapor inside the device.

[0057] The method for producing the formulation of the present invention includes the following steps: Formula (I): [ka] or a pharmaceutically acceptable salt thereof, the method for producing a freeze-dried preparation comprising at least the following steps: Step 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber to a predetermined cooling temperature; and Step 2) spraying mist into the chamber; is.

[0058] Another embodiment of the method for producing the formulation of the present invention is a method for producing a lyophilized formulation, which comprises at least the following steps of lyophilizing a solution containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof: Step 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber to a predetermined cooling temperature; step 2) spraying a mist into the chamber; and Step 3) further cooling; is.

[0059] Another embodiment of the method for producing the formulation of the present invention is a method for producing a lyophilized formulation, which comprises at least the following steps of lyophilizing a solution containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof: Step 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; and Step 4) maintaining the temperature at or above the glass transition temperature; is.

[0060] Another embodiment of the method for producing the formulation of the present invention is a method for producing a lyophilized formulation, which comprises at least the following steps of lyophilizing a solution containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof: Step 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; Step 4) maintaining the temperature at or above the glass transition temperature; and 5) Drying process is.

[0061] In the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) Formula (I): [ka] or a pharmaceutically acceptable salt thereof, b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; and Step 2) spraying mist into the chamber; is.

[0062] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; step 2) spraying a mist into the chamber; and Step 3) further cooling; is.

[0063] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; and Step 4) maintaining the temperature at or above the glass transition temperature; is.

[0064] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; Step 4) maintaining the temperature at or above the glass transition temperature; and Step 5) drying step; is.

[0065] In the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; and Step 2) spraying mist into the chamber; is.

[0066] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; step 2) spraying a mist into the chamber; and Step 3) Further cooling is.

[0067] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; and Step 4) maintaining the temperature at or above the glass transition temperature; is.

[0068] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; Step 4) maintaining the temperature at or above the glass transition temperature; and Step 5) drying step; is.

[0069] The method for producing the formulation of the present invention includes the following steps: Formula (II): [ka] A method for producing a freeze-dried preparation, comprising at least the following steps of freeze-drying a solution containing a sodium salt represented by the formula: Step 1) cooling the solution containing the sodium salt of formula (II) in the freeze-dryer chamber to a predetermined cooling temperature; and Step 2) spraying mist into the chamber; is.

[0070] Another embodiment of the method for producing the formulation of the present invention is a method for producing a freeze-dried formulation, which comprises at least the following steps of freeze-drying a solution containing the sodium salt represented by formula (II): Step 1) cooling the solution containing the sodium salt of formula (II) in the freeze-dryer chamber to a predetermined cooling temperature; step 2) spraying a mist into the chamber; and Step 3) further cooling; is.

[0071] Another embodiment of the method for producing the formulation of the present invention is a method for producing a freeze-dried formulation, which comprises at least the following steps of freeze-drying a solution containing the sodium salt represented by formula (II): Step 1) cooling the solution containing the sodium salt of formula (II) in the freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; and Step 4) maintaining the temperature at or above the glass transition temperature; is.

[0072] Another embodiment of the method for producing the formulation of the present invention is a method for producing a freeze-dried formulation, which comprises at least the following steps of freeze-drying a solution containing the sodium salt represented by formula (II): Step 1) cooling a solution containing the compound of formula (II) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; Step 4) maintaining the temperature at or above the glass transition temperature; and Step 5) Drying is.

[0073] In the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) Formula (II): [ka] a sodium salt represented by b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; and Step 2) spraying mist into the chamber; is.

[0074] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a sodium salt of formula (II), b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; step 2) spraying a mist into the chamber; and Step 3) further cooling; is.

[0075] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a sodium salt of formula (II), b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; and Step 4) maintaining the temperature at or above the glass transition temperature; is.

[0076] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a sodium salt of formula (II), b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; Step 4) maintaining the temperature at or above the glass transition temperature; and Step 5) drying step; is.

[0077] In the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a sodium salt of formula (II), b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; and Step 2) spraying mist into the chamber; is.

[0078] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a sodium salt of formula (II), b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; step 2) spraying a mist into the chamber; and Step 3) Further cooling is.

[0079] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a sodium salt of formula (II), b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; and Step 4) maintaining the temperature at or above the glass transition temperature; is.

[0080] In another embodiment of the method for producing the formulation of the present invention, the liquid to be lyophilized contains at least the following components: a) a sodium salt of formula (II), b) sodium chloride, and, c) sucrose and a method for producing a freeze-dried preparation, the method comprising at least the following steps of freeze-drying the liquid containing the compound: Step 1) cooling the containing liquid in a freeze-dryer chamber to a predetermined cooling temperature; Step 2) spraying mist into the chamber; Step 3) further cooling; Step 4) maintaining the temperature at or above the glass transition temperature; and Step 5) drying step; is.

[0081] Hereinafter, the temperature in the process of the present invention refers to the shelf temperature in the freeze-dryer, which is approximately equal to the product temperature of the vials in the freeze-dryer.

[0082] The cooling temperature in step 1) of the production method of the present invention is usually −30° C. to −5° C., preferably −25° C. to −8° C., and more preferably −22° C. to −10° C. If the temperature is lower than this range, the ice nuclei will be small and the pore size of the freeze-dried preparation will be small, which may hinder water penetration and prolong the time required for redissolution in water. If the temperature is higher than this range, the water content will be high and there is a risk of decomposition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0083] The time for step 1) of the production method of the present invention is usually 0.1 to 4 hours, preferably 0.25 to 3.5 hours, and more preferably 0.5 to 3 hours. If the time is shorter than this range, the product temperature may not be sufficiently cooled, and if the time is longer than this range, the cooling time may become too long, and it may take a long time to complete the lyophilized preparation.

[0084] The cooling rate in step 1) of the production method of the present invention is usually 0.01° C. to 2° C. / min, preferably 0.05° C. to 1.5° C. / min, and more preferably 0.1° C. to 1° C. / min. If the cooling rate is faster than this, there is a risk of variation in product temperature between vials, and if the cooling rate is slower than this, there is a risk of the cooling time becoming too long and it taking a long time to complete the lyophilized preparation.

[0085] The mist sprayed in step 2) of the present invention is ice fog. The raw material for this ice fog is one or more selected from the group consisting of nitrogen, water vapor, argon, helium, air, oxygen, carbon dioxide, neon, xenon, krypton, and hydrogen. Preferably, nitrogen and water vapor (pure steam) are used as raw materials to produce ice fog. Both nitrogen and water vapor (pure steam) are sprayed into the freeze dryer from a nozzle.

[0086] The resulting ice mist is rapidly introduced into a freeze-drying chamber, causing ice nucleation of all the product in the different vials within the chamber.

[0087] The ice crystals themselves can act as nucleating agents for ice formation in supercooled aqueous solutions. In this "ice fog" method, a freeze dryer is filled with ice fog, creating a gas-phase suspension of tiny ice particles. These particles are then transferred into a glass bottle, where they initiate ice nucleation when they come into contact with a fluid interface.

[0088] In step 2) of the process of the present invention, in which the ice mist is sprayed, the cooling temperature is usually −30° C. to −5° C., preferably −25° C. to −8° C., and more preferably −22° C. to −10° C. If the temperature is lower than this range, the ice nuclei will be small and the pore size (pore diameter) of the freeze-dried preparation will be small, which may hinder water penetration and prolong the time required for redissolution in water. If the temperature is higher than this range, the water content will be high and there is a risk of decomposition of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0089] The cooling rate in step 2) of the production method of the present invention is usually 0.01°C to 2°C / min, preferably 0.05°C to 1.5°C / min, and more preferably 0.1°C to 1°C / min. If the cooling rate is faster than this, the particle size of the ice nuclei will be smaller, and the pore size (pore diameter) of the freeze-dried preparation will be smaller, which may make it difficult for water to penetrate and extend the time required for redissolution in water. If the cooling rate is slower than this, the cooling time will be longer, and it may take a long time to complete the freeze-dried preparation.

[0090] The cooling temperature in step 3) of the present invention may be any temperature at which the aqueous solution can be frozen, and is generally -80°C to -30°C, preferably -70°C to -35°C, and more preferably -60°C to -40°C.

[0091] The time for step 3) of the present invention may be any time that allows the aqueous solution to freeze, and is generally 2 to 8 hours, preferably 2.5 to 7.5 hours, and more preferably 3 to 7 hours.

[0092] The cooling rate in step 3) of the production method of the present invention is usually 0.01°C to 2°C / min, preferably 0.05°C to 1.5°C / min, and more preferably 0.1°C to 1.0°C / min.

[0093] When a conventional freeze-drying process is unable to achieve sufficient solute crystallization or the desired polymorph, an effective method for promoting crystallization in the frozen solution is to heat and maintain the product temperature above the glass transition temperature (Tg') of the most concentrated phase before decompression begins, i.e., "annealing." Annealing promotes solute crystallization and also increases the size of ice crystals through Ostwald ripening, thereby increasing the water vapor flow path, which is the rate-limiting factor in primary drying. This shortens the freeze-drying time and reduces energy consumption. The "annealing" step (step 4) of the present invention, in which the solution is heated and maintained above the glass transition temperature, can crystallize sodium sulfate in the pharmaceutical formulation of the present invention.

[0094] The cooling temperature in step 4) of the present invention may be higher than the cooling temperature in step 3), but is generally -40°C to -10°C, preferably -35°C to -15°C, and more preferably -30°C to -20°C.

[0095] The time required for step 4) in the production method of the present invention is usually 0.1 to 4 hours, preferably 0.25 to 3.5 hours, and more preferably 0.5 to 3 hours.

[0096] The cooling rate in step 4) of the production method of the present invention is usually 0.01°C to 2°C / min, preferably 0.05°C to 1.5°C / min, and more preferably 0.1°C to 1°C / min.

[0097] The drying step (step 5) of the present invention can be divided into two steps: primary drying, in which the frozen sample is sublimated under vacuum, and secondary drying, in which the sample is heated to a temperature that does not affect the sample and removes the intermolecularly bound water (bound water). The temperature for primary drying is usually −30°C to −1°C, preferably −25°C to −2.5°C, and more preferably −20°C to −5°C.

[0098] The time for primary drying in the production method of the present invention depends on the size of the freeze-dryer, but is usually 70 to 100 hours, preferably 75 to 95 hours, and more preferably 80 to 90 hours.

[0099] The vacuum pressure for primary drying in the production method of the present invention is usually 1 to 50 Pa, preferably 2.5 to 40 Pa, and more preferably 5 to 20 Pa.

[0100] The temperature for secondary drying in the production method of the present invention is usually 30°C to 80°C, preferably 35°C to 75°C, and more preferably 40°C to 70°C.

[0101] The secondary drying time in the production method of the present invention depends on the size of the freeze-dryer, but is usually 1 to 15 hours, preferably 2.5 to 12 hours, and more preferably 5 to 10 hours.

[0102] The vacuum pressure for secondary drying in the production method of the present invention is usually 1 to 50 Pa, preferably 2.5 to 40 Pa, and more preferably 5 to 20 Pa.

[0103] In the production method of the present invention, a re-cooling step may be inserted between step 4) and step 5. The re-cooling temperature is usually -80°C to -10°C, preferably -70°C to -20°C, and more preferably -60°C to -30°C.

[0104] The time for the re-cooling step is usually 0.25 to 3 hours, preferably 0.5 to 2.5 hours, and more preferably 0.75 to 2 hours.

[0105] In the process of the present invention, the cooling temperature, process time, and cooling rate for the combined steps 1) and 2) are generally -30°C to -5°C, 0.1 to 4 hours, and 0.01 to 2°C / min for the step 1), and -30°C to -5°C and 0.01 to 2°C / min for the step 2), preferably -25°C to -8°C, 0.1 to 4 hours, and 0.01 to 2°C / min for the step 2). The cooling time in step 1) is 0.25 to 3.5 hours, with a cooling rate of 0.05°C to 1.5°C / min, and the cooling temperature in step 2) is -25°C to -8°C and the cooling rate is 0.05°C to 1.5°C / min, and more preferably the cooling temperature in step 1) is -22°C to -10°C, the process time is 0.5 to 3 hours, with a cooling rate of 0.1°C to 1°C / min, and the cooling temperature in step 2) is -22°C to -10°C and the cooling rate is 0.1°C to 1°C / min. Furthermore, in step 2), ice mist is sprayed into the freeze dryer.

[0106] In the production method of the present invention, the cooling temperature, process time and cooling rate for the combination of steps 1), 2) and 3) are usually -30°C to -5°C, 0.1 to 4 hours and 0.01°C to 2°C / min for step 1), -30°C to -5°C and 0.01°C to 2°C / min for step 2), -80°C to -30°C, 2 to 8 hours and 0.01°C to 2°C / min for step 3), and preferably -25°C to -8°C, 0.25 to 3.5 hours and 0.05 to 1.5°C for step 1). In step 2), the cooling temperature is -25°C to -8°C and the cooling rate is 0.05°C to 1.5°C / min, and in step 3), the cooling temperature is -70°C to -35°C, the process time is 2.5 hours to 7.5 hours, and the cooling rate is 0.05°C to 1.5°C / min, and more preferably, in step 1), the cooling temperature is -22°C to -10°C, the process time is 0.5 hours to 3 hours, and the cooling rate is 0.1°C to 1°C / min, in step 2), the cooling temperature is -22°C to -10°C and the cooling rate is 0.1°C to 1°C / min, and in step 3), the cooling temperature is -60°C to -40°C, the process time is 3 hours to 7 hours, and the cooling rate is 0.1°C to 1.0°C / min. Furthermore, in step 2), ice mist is sprayed into the freeze dryer.

[0107] In the method of the present invention, the cooling temperature, process time, and cooling rate for the combination of steps 1), 2), 3), and 4) are usually as follows: in step 1), the cooling temperature is -30°C to -5°C, the process time is 0.1 hours to 4 hours, and the cooling rate is 0.01°C to 2°C / min; in step 2), the cooling temperature is -30°C to -5°C, and the cooling rate is 0.01°C to 2°C / min; in step 3), the cooling temperature is -80°C to -30°C, and the process time is 0.01°C to 2°C / min; The cooling time is 2 hours to 8 hours, and the cooling rate is 0.01°C to 2°C / min, and the cooling temperature in step 4) is -40°C to -10°C, the process time is 0.1 hours to 4 hours, and the cooling rate is 0.01°C to 2°C / min, preferably the cooling temperature in step 1) is -25°C to -8°C, the process time is 0.25 hours to 3.5 hours, and the cooling rate is 0.05°C to 1.5°C / min, and the cooling temperature in step 2) is -25°C to -8°C, and the cooling rate is 0. the cooling temperature in step 3) is -70°C to -35°C, the process time is 2.5 hours to 7.5 hours, and the cooling rate is 0.05°C to 1.5°C / min; the cooling temperature in step 4) is -35°C to -15°C, the process time is 0.25 hours to 3.5 hours, and the cooling rate is 0.05°C to 1.5°C / min; more preferably, the cooling temperature in step 1) is -22°C to -10°C, and the process time is 0.5 hours to The cooling time is 3 hours, with a cooling rate of 0.1°C to 1°C / min, the cooling temperature in step 2) is -22°C to -10°C, with a cooling rate of 0.1°C to 1°C / min, the cooling temperature in step 3) is -60°C to -40°C, the process time is 3 hours to 7 hours, with a cooling rate of 0.1°C to 1.0°C / min, and the cooling temperature in step 4) is -30°C to -20°C, with a process time of 0.5 hours to 3 hours, with a cooling rate of 0.1°C to 1.0°C / min. Furthermore, in step 2), ice mist is sprayed into the freeze dryer.

[0108] In the production method of the present invention, the cooling temperature, process time and cooling rate for the combination of steps 1), 2), 3), 4) and 5) are usually as follows: in step 1), the cooling temperature is -30°C to -5°C, the process time is 0.1 hours to 4 hours, and the cooling rate is 0.01°C to 2°C / min; in step 2), the cooling temperature is -30°C to -5°C, and the cooling rate is 0.01°C to 2°C / min; in step 3), the cooling temperature is -80°C to -30°C, the process time is 2 hours to 8 hours, and the cooling rate is 0.01°C to 2°C / min; in step 4), the cooling temperature is -40°C to -10°C, the process time is 0.1 hours to 4 hours, and the cooling rate is 0.01°C to 2°C / min; The primary drying temperature in step 1) is -30°C to -1°C, the primary drying time is 70 hours to 100 hours, the vacuum pressure in the primary drying is 1 to 50 Pa, the secondary drying temperature is 30°C to 80°C, the secondary drying time is 1 to 15 hours, and the vacuum pressure in the secondary drying is 1 to 50 Pa; preferably, the cooling temperature in step 1) is -25°C to -8°C, the process time is 0.25 hours to 3.5 hours, and the cooling rate is 0.05°C to 1.5°C / min, the cooling temperature in step 2) is -25°C to -8°C, and the cooling rate is 0.05°C to 1.5°C / min, and the cooling temperature in step 3) is -70°C to -35°C, the process time is 2.5 hours to 7.5 hours, and the cooling rate is 0. the cooling temperature in step 1) is -22°C to -10°C, the process time is 0.5 hours to 3 hours, and the cooling rate is 0.1°C to 1°C / min; the cooling temperature in step 2) is -35°C to -15°C, the process time is 0.25 hours to 3.5 hours, and the cooling rate is 0.05°C to 1.5°C / min; the primary drying temperature in step 3) is -25°C to -2.5°C, the primary drying time is 75 hours to 95 hours, the vacuum pressure in primary drying is 2.5 to 40 Pa, the secondary drying temperature is 35°C to 75°C, the secondary drying time is 2.5 to 12 hours, and the vacuum pressure in secondary drying is 2.5 to 40 Pa; more preferably, the cooling temperature in step 1) is -22°C to -10°C, the process time is 0.5 hours to 3 hours, and the cooling rate is 0.1°C to 1°C / min; the cooling temperature in step 1) is -22°C to -10°C and the cooling rate is 0.1°C to 1°C / min; the cooling temperature in step 2) is -60°C to -40°C and the process time is 3 to 7 hours and the cooling rate is 0.1°C to 1.0°C / min; the cooling temperature in step 3) is -30°C to -20°C and the process time is 0.5 to 3 hours and the cooling rate is 0.1°C to 1.0°C / min; the primary drying temperature in step 5) is -20°C to -5°C and the primary drying time is 80 to 90 hours and the vacuum pressure in the primary drying is 5 to 20 Pa; the secondary drying temperature is 40°C to 70°C and the secondary drying time is 5 to 10 hours and the vacuum pressure in the secondary drying is 5 to 20 Pa.Furthermore, in step 2), ice mist is sprayed into the freeze dryer.

[0109] As a method for producing the solution before freeze-drying, 1) Formula (I): [ka] or a pharmaceutically acceptable salt thereof with an alkaline substance to adjust the pH to 5 to 6; 2) mixing the liquid produced in step 1), component b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride, and component c) sugar and / or sugar alcohol; The solution before freeze-drying can be produced by a production method including the following steps: Component b) is preferably sodium chloride, and component c) is preferably sucrose.

[0110] As a method for producing a solution containing the substance before freeze-drying, it is more preferable to include at least the following steps: 1) adjusting the pH of a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof to 5.5 to 6 with an alkaline substance; and 2) mixing the liquid produced in step 1), component b) and component c); (wherein components b) and c) have the same meanings as above.) The solution containing the compound before freeze-drying can be produced by the production method.

[0111] More preferably, the method for producing the pre-lyophilized solution comprises at least the following steps: 1) adjusting a suspension of the compound of formula (I) or a pharmaceutically acceptable salt thereof to pH 5 to 6 with sodium hydroxide; and 2) A step of mixing the liquid produced in step 1), component b) and component c). (wherein components b) and c) have the same meanings as above.) The solution containing the compound before freeze-drying can be produced by the production method.

[0112] More preferably, at least the following steps: 1) adjusting a suspension of the compound of formula (I) or a pharmaceutically acceptable salt thereof to pH 5.5 to 6 with sodium hydroxide; and 2) A step of mixing the liquid produced in step 1), component b) and component c). (wherein components b) and c) have the same meanings as above.) The solution containing the compound before freeze-drying can be produced by the production method.

[0113] More preferably, at least the following steps: 1) adjusting a suspension of p-toluenesulfonate and sulfate of the compound of formula (I) to a pH of 5.5 to 6 with sodium hydroxide; and 2) A step of mixing the liquid produced in step 1), component b) and component c) (where components b) and c) have the same meanings as above) can be used to produce a liquid containing the liquid before freeze-drying.

[0114] The formulation of the present invention is produced by the following steps: 1) adding the compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably the p-toluenesulfonate or sulfate salt of the compound of formula (I), to water for injection to prepare an acidic slurry; 2) adding aqueous sodium hydroxide to the slurry from 1) to adjust the pH to 5.5 to 6, and adding the stabilizing additives described above; 3) adding additional water for injection to adjust the concentration to 10 w / w%, adjusting the pH to 5 to 6, and then sterile filtering to obtain a formulation; 4) dispensing a certain amount of the formulation from 3) into vials, ampoules, etc., and lyophilizing the formulation. The production of the formulation of the present invention is preferably carried out under sealed conditions.

[0115] Sterile filtration can be performed by a sterile filtration filter.

[0116] The vial may be a transparent glass vial with a capacity of approximately 5 to 20 mL, such as a BVK type vial.

[0117] The lyophilized formulation of the present invention is dissolved in a solvent such as distilled water for injection, physiological saline, or glucose solution before administration. The formulation of the present invention exhibits a strong antibacterial spectrum against gram-positive and gram-negative bacteria, and particularly exhibits strong antibacterial activity against β-lactamase-producing gram-negative bacteria, and does not exhibit cross-resistance with existing cephem or carbapenem drugs.

[0118] The formulation of the present invention containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the sodium salt represented by formula (II) is administered as an injection.

[0119] The manufacturing method of the present invention allows the specific surface area of ​​the formulation of the present invention to be controlled. The specific surface area can be controlled by the cooling temperature and cooling rate when spraying the ice mist. If the cooling temperature when spraying the ice mist is high, the particle size of the ice nuclei when frozen will be large, and if the cooling temperature when spraying the ice mist is low, the particle size of the ice nuclei when frozen will be small. Also, if the cooling rate is fast, the particle size of the ice nuclei when frozen will be small. Small If the cooling rate is slow, the particle size of the ice nuclei will become larger during freezing.

[0120] During primary drying, vapor sublimes from the ice nuclei, turning the ice nuclei into pores in the freeze-dried formulation. Therefore, if the particle size of the ice nuclei increases during freezing, the pores in the freeze-dried formulation that are the ice nuclei's remains will become larger, and if the particle size of the ice nuclei decreases during freezing, the pores in the freeze-dried formulation that are the ice nuclei's remains will become smaller.

[0121] If the pores of a freeze-dried formulation are larger, the specific surface area will be smaller, but the rate at which water penetrates into the freeze-dried formulation will be faster, shortening the dissolution time of the freeze-dried formulation, i.e., the reconstitution time. On the other hand, if the pores of a freeze-dried formulation are smaller, the specific surface area will be larger, but the rate at which water penetrates into the freeze-dried formulation will be slower, lengthening the dissolution time of the freeze-dried formulation, i.e., the reconstitution time.

[0122] "Reconstitution time" refers to the time required for the lyophilized molecule to dissolve and / or suspend in liquid form. For example, reconstitution time includes, but is not limited to, the time required for a lyophilized formulation containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof to become suspended in water or a buffer solution after lyophilization.

[0123] The reconstitution time for the formulation of the present invention is generally 30 seconds or less, preferably 28 seconds or less, and more preferably 25 seconds or less.

[0124] When the pores of a freeze-dried preparation become larger, i.e., when the specific surface area becomes smaller, the water content in the freeze-dried preparation increases, and there is a risk that a compound that is easily decomposed by water, such as the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, may decompose and produce analogs. On the other hand, when the pores of a freeze-dried preparation become smaller, i.e., when the specific surface area becomes larger, there is a risk that a compound that is easily decomposed by water, such as the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, may not decompose, and there is little risk of producing analogs.

[0125] The water content of the formulation of the present invention should be 0.5% or less. If the water content is higher than this, there is a risk that the amount of analogues will increase to above the standard value when stored in a refrigerator (2 to 8°C) for 4 years.

[0126] In order to optimize the reconstitution time and moisture content, the specific surface area of ​​the formulation of the present invention is set to 0.6 m 2 / g~1.1m 2 / g, preferably 0.625m 2 / g~1.1m 2 / g, more preferably 0.65m 2 / g~1.1m 2 / g. If the specific surface area is larger than this range, the reconstitution time may be longer, and if the specific surface area is smaller than this range, the moisture content may be higher. A lyophilized preparation having the above-mentioned specific surface area may be produced by the production method of the present invention, but can also be produced by methods other than the production method of the present invention. As long as the lyophilized preparation has the above-mentioned specific surface area, the above-mentioned optimal reconstitution time and moisture content can be achieved even if it is not produced by the production method of the present invention.

[0127] When freeze-drying a large number of vials, the specific surface area of ​​the freeze-dried preparation may vary from one vial to another. However, with the method of the present invention, the variation in the specific surface area of ​​the freeze-dried preparation from one vial to another is small, typically within 0.3 m 2 / g or less, preferably 0.25m 2 / g or less, more preferably 0.2m 2 / g or less.

[0128] If the moisture content in the freeze-dried preparation containing the compound represented by formula (I) is higher than 0.5%, there is a risk that the amount of analogues will increase when stored in a refrigerator (2 to 8°C) for 4 years. Such analogues are mainly compounds represented by formula (III): [ka] The compound represented by formula (III) is preferably present in a low amount in consideration of toxicity, and the allowable content of the compound represented by formula (III) in a freeze-dried formulation after 4 years of storage at refrigeration (2 to 8°C) is 1.30% or less peak area ratio (liquid chromatography).

[0129] Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m 2 / g, the reconstitution time is within 30 seconds, the moisture content is 0.5% or less, and preferably the specific surface area of ​​the freeze-dried preparation is 0.625 to 1.1 m 2 / g, the reconstitution time is within 28 seconds and the moisture content is 0.5% or less, and more preferably, the specific surface area of ​​the freeze-dried preparation is 0.65 to 1.1 m 2 / g, the reconstitution time is within 25 seconds and the moisture content is 0.5% or less.

[0130] At least the following ingredients: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols A freeze-dried preparation containing the compound, wherein the specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m 2 / g, the reconstitution time is within 30 seconds, the moisture content is 0.5% or less, and preferably the specific surface area of ​​the freeze-dried preparation is 0.625 to 1.1 m 2 / g, the reconstitution time is within 28 seconds and the moisture content is 0.5% or less, and more preferably, the specific surface area of ​​the freeze-dried preparation is 0.65 to 1.1 m 2 / g, the reconstitution time is within 25 seconds and the moisture content is 0.5% or less.

[0131] At least the following ingredients: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) sodium chloride, and, c) sucrose A freeze-dried preparation containing the compound, wherein the specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m 2 / g, the reconstitution time is within 30 seconds, the moisture content is 0.5% or less, and preferably the specific surface area of ​​the freeze-dried preparation is 0.625 to 1.1 m 2 / g, the reconstitution time is within 28 seconds and the moisture content is 0.5% or less, and more preferably, the specific surface area of ​​the freeze-dried preparation is 0.65 to 1.1 m 2 / g, the reconstitution time is within 25 seconds and the moisture content is 0.5% or less.

[0132] Formula (II): [ka] A freeze-dried preparation containing a sodium salt represented by the formula: 2 / g, the reconstitution time is within 30 seconds, the moisture content is 0.5% or less, and preferably the specific surface area of ​​the freeze-dried preparation is 0.625 to 1.1 m 2 / g, the reconstitution time is within 28 seconds and the moisture content is 0.5% or less, and more preferably, the specific surface area of ​​the freeze-dried preparation is 0.65 to 1.1 m 2 / g, the reconstitution time is within 25 seconds and the moisture content is 0.5% or less.

[0133] At least the following ingredients: a) a sodium salt of formula (II), b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols A freeze-dried preparation containing the compound, wherein the specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m 2 / g, the reconstitution time is within 30 seconds, the moisture content is 0.5% or less, and preferably the specific surface area of ​​the freeze-dried preparation is 0.625 to 1.1 m 2 / g, the reconstitution time is within 28 seconds and the moisture content is 0.5% or less, and more preferably, the specific surface area of ​​the freeze-dried preparation is 0.65 to 1.1 m 2 / g, the reconstitution time is within 25 seconds and the moisture content is 0.5% or less.

[0134] At least the following ingredients: a) a sodium salt of formula (II), b) sodium chloride, and, c) sucrose A freeze-dried preparation containing the compound, wherein the specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m2 / g, the reconstitution time is within 30 seconds, the moisture content is 0.5% or less, and preferably the specific surface area of ​​the freeze-dried preparation is 0.625 to 1.1 m 2 / g, the reconstitution time is within 28 seconds and the moisture content is 0.5% or less, and more preferably, the specific surface area of ​​the freeze-dried preparation is 0.65 to 1.1 m 2 / g, the reconstitution time is within 25 seconds and the moisture content is 0.5% or less. [Example]

[0135] EXAMPLES The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these examples. 1. Method for producing the compound of formula (I) or a pharmaceutically acceptable salt thereof (1.3 molar equivalents of tosylate and 0.4 molar equivalents of sulfate) For example, synthesis can be performed with reference to International Publication Nos. 2016 / 035845 and 2016 / 035846. <Synthesis of Seed Crystal A of 2 Molar Equivalents of p-Toluenesulfonate of the Compound Represented by Formula (I)> Formula (I) (100 mg) was dissolved in 1.0 mol / L aqueous p-toluenesulfonic acid solution (2 mL) at room temperature using ultrasonic waves, and the solution was allowed to stand at 4°C for 4 days. The precipitate was filtered to obtain seed crystal A (73 mg). The crystals were confirmed to be needle-like crystals under a microscope. <Synthesis of hydrate crystals of a mixed acid salt of the compound represented by formula (I) with 1.3 molar equivalents of p-toluenesulfonic acid and 0.35 molar equivalents of sulfuric acid (hereinafter referred to as "form I crystals")> Step 1: Synthesis of seed crystal C Seed crystal A (50 mg) was dissolved in 6 mol / L H2SO4 (3 mL) at room temperature in an ultrasonic bath and allowed to stand at 4 °C for 2 days. The precipitated crystalline solid was filtered and washed with ice-cold water to obtain seed crystal C (23 mg). Step 2: Synthesis of Compound 5 [ka] The abbreviations used herein are defined as follows: Boc: t-butoxycarbonyl PMB: p-methoxybenzyl Under a nitrogen atmosphere, compound 1 (18.0 kg, 22.6 mol) was dissolved in N,N-dimethylacetamide (41 L) and cooled to 0°C. Sodium iodide (6.8 kg, 45.2 mol), compound 2 (13.1 kg, 24.9 mol), and N,N-dimethylacetamide (4 L) were added and stirred at 0°C for 6 hours. The temperature was raised to 7°C and the mixture was stirred for 16 hours. The mixture was cooled to 0°C, sodium iodide (5.1 kg, 33.9 mol) was added, and then acetyl chloride (8.9 kg, 113.0 mol) was added dropwise at 0°C over 90 minutes and stirred at 0°C for 5 hours. Anisole (36 L) was added to the reaction mixture, and this mixture was added to a mixture of methyl ethyl ketone and aqueous sodium hydrogen sulfite solution for extraction. The organic layer was washed twice with a mixture of sulfuric acid and brine. Anisole (90 L) was added, the mixture was cooled to 15°C, and 75% sulfuric acid (36.0 kg) was added, followed by stirring at 28°C for 2 hours. Water (90 L) and ethyl acetate (36 L) were added for extraction. The resulting aqueous layer was washed twice with ethyl acetate and then washed with a small particle size synthetic adsorbent for chromatographic separation (Diaion). TM The compound was purified by reverse-phase column chromatography (acetonitrile-sulfuric acid aqueous solution) using a HPLC HP20SS column. An aqueous solution of 75% sulfuric acid (33.4 kg) and p-toluenesulfonic acid monohydrate (16.7 kg) was added to the resulting eluate, followed by the addition of an appropriate amount of seed crystal C to precipitate a solid. The mixture was cooled to 5°C and stirred at 5°C for 10 hours. The precipitated crystalline solid was filtered. The crystalline solid was washed with water cooled to 5°C and then dried under reduced pressure to obtain Form I crystals of Compound 5, i.e., the p-toluenesulfonate sulfate salt (1.3 molar equivalents of tosylate / 0.35 molar equivalents of sulfate) (12.7 kg, 49% yield based on content) of the compound represented by Formula (I).

[0136] The contents of p-toluenesulfonic acid and sulfuric acid in the type I crystal were determined by the following method. (Method for measuring p-toluenesulfonic acid content) Step 1: Preparation of sample solution Approximately 40 mg of sample was accurately weighed and dissolved in sample dilution solvent to make exactly 25 mL. 2 mL of this solution was accurately measured and the sample dilution solvent was added to make exactly 20 mL. Step 2: Preparation of standard solutions Approximately 25 mg of sodium p-toluenesulfonate standard was accurately weighed out and dissolved in sample dilution solvent to make exactly 100 mL. 5 mL of this solution was accurately measured and the sample dilution solvent was added to make exactly 50 mL. The sample dilution solvent used was a 5 mmol / L phosphate buffer / liquid chromatography grade acetonitrile mixture (9:1), where the phosphate buffer was a mixture of water, 0.05 mol / L sodium dihydrogen phosphate TS, and 0.05 mol / L disodium hydrogen phosphate TS = 18:1:1 (pH approximately 7.1). Step 3: Measurement and quantification The sample solution and standard solution were analyzed by liquid chromatography under the following test conditions, and the peak area of ​​p-toluenesulfonic acid was measured by automatic integration. Note that the dehydrated product equivalent is a value calculated by subtracting the water content from the total amount, assuming that this is 100%. The mobile phase gradient program is shown in Table 1. (Test conditions) Column: Unison UK-C18, φ4.6 × 150 mm, 3 μm, manufactured by Imtakt Column temperature: constant temperature around 35°C Flow rate: 1.0 mL per minute (retention time of p-toluenesulfonic acid: approx. 7 minutes) Detector: UV spectrophotometer (measurement wavelength: 218 nm) Mobile phase A: 0.1% trifluoroacetic acid solution Mobile phase B: Acetonitrile for liquid chromatography

[0137] [Table 1] The content of p-toluenesulfonic acid in the sample was calculated using the following formula: Amount of p-toluenesulfonic acid (%) TIFF0007792906000020.tif15112 M S : Amount of sodium p-toluenesulfonate standard (mg) M T :Weighted amount of sample (mg) P: Purity of sodium p-toluenesulfonate standard (%) W T : Moisture content of sample (%) A T : Peak area of ​​p-toluenesulfonic acid obtained from the sample solution A S : Peak area of ​​p-toluenesulfonic acid obtained from standard solution 172.20: Molecular weight of p-toluenesulfonic acid 194.18: Molecular weight of sodium p-toluenesulfonate TIFF0007792906000021.tif15142

[0138] (Method for measuring sulfuric acid content) Step 1: Preparation of standard solutions Approximately 50 mg of anhydrous sodium sulfate was accurately weighed and dissolved in mobile phase to make exactly 25 mL. 2 mL of this solution was accurately measured and the mobile phase was added to make exactly 50 mL. 2 mL of this solution was then accurately measured and the mobile phase was added to make exactly 20 mL. Step 2: Preparation of sample solution Approximately 30 mg of sample was accurately weighed and dissolved in mobile phase to make exactly 25 mL. 2 mL of this solution was accurately measured and the mobile phase was added to make exactly 20 mL. Step 3: Measurement and quantification The sample solution and the standard solution were measured by liquid chromatography (ion chromatography) under the following test conditions, and the peak area of ​​sulfate ion was measured by automatic integration. (Test conditions) Column: Shim-pack IC-A3, φ4.6 × 150 mm, 5 μm, Shimadzu Corporation Column temperature: constant temperature around 40°C Flow rate: 1.2 mL per minute (sulfate ion retention time: approximately 15 minutes) Detector: Electrical conductivity detector (non-suppressor type) Mobile phase: Accurately weigh approximately 0.67 g of Bis-Tris, approximately 3.09 g of boric acid, and approximately 1.11 g of crushed p-hydroxybenzoic acid, and dissolve them in water to make exactly 1000 mL. The sulfuric acid content in the sample was calculated using the following formula: Amount of sulfuric acid (%) = M S / M T × 100 / (100-W T ) × A T / A S × 98.08 / 142.04 × 1 / 25 × 100 M S : Amount of anhydrous sodium sulfate (mg) M T :Weighted amount of sample (mg) W T : Moisture content of sample (%) A S : Peak area of ​​sulfate ion obtained from standard solution A T : Peak area of ​​sulfate ions obtained from the sample solution 98.08: Molecular weight of sulfuric acid 142.04: Molecular weight of anhydrous sodium sulfate 1 / 25: Dilution ratio (result) p-Toluenesulfonic acid: 22.2% ± 0.2% (dehydrate equivalent) Sulfuric acid: 4.3%±0.1% (calculated as dehydrated product)

[0139] Elemental analysis: (C 30 H 34 N7ClO 10 (calculated as S2 1.32C7H8O3S 0.45H2SO4 9.0H2O) Calculated values: C 39.75(%), H 5.39(%), N 8.27(%), C1 2.99(%), S 10.19(%), H2O 13.67(%) Measured values: C 39.73(%), H 5.33(%), N 8.53(%), C1 3.08(%), S 10.11(%), H2O (KF method) 13.69(%) The resulting crystals are hydrate crystals of a mixed acid salt of 1.3 molar equivalents of p-toluenesulfonic acid and 0.35 molar equivalents of sulfuric acid of the compound of formula (I), with approximately 0.02 molar equivalents of p-toluenesulfonic acid and approximately 0.1 molar equivalents of sulfuric acid remaining in the form of type I crystals. Even in the case of type I crystals with additional p-toluenesulfonic acid and / or sulfuric acid remaining, the characteristic powder X-ray diffraction pattern of type I crystals remains unchanged, and the crystals can exist stably as crystals substantially identical to type I crystals. Type I crystals may also contain approximately 0.01 to 0.1 molar equivalents of p-toluenesulfonic acid and / or approximately 0.01 to 0.1 molar equivalents of sulfuric acid remaining. The residual acid may be attached to the crystals or incorporated within the crystals. The preferred p-toluenesulfonic acid content of the I-type crystals is about 20.2±0.2 to 23.2±0.2% (dehydrate equivalent), and the preferred sulfuric acid content is about 3.5±0.1 to 5.0±0.1% (dehydrate equivalent). The more preferred p-toluenesulfonic acid content of the I-type crystals is about 21.5±0.2 to 22.3±0.2% (dehydrate equivalent), and the more preferred sulfuric acid content is about 4.2±0.1 to 4.9±0.1% (dehydrate equivalent). The even more preferred p-toluenesulfonic acid content of the I-type crystals is about 21.5 to 22.3% (dehydrate equivalent), and the even more preferred sulfuric acid content is about 4.2 to 4.9% (dehydrate equivalent).

[0140] 2. Method for producing a liquid containing the sodium salt represented by formula (II), sodium p-toluenesulfonate, and sodium sulfate For example, it can be produced by referring to International Publication Nos. 2016 / 035845 and 2016 / 035846. The sodium salt of formula (II) (hereinafter sometimes abbreviated as "Na salt of formula (II)"), sodium p-toluenesulfonate (hereinafter sometimes abbreviated as "Na tosylate"), and sodium sulfate (hereinafter sometimes abbreviated as "Na sulfate") were prepared by the following method. Specifically, 1000 mg of the compound of formula (I) or its pharmaceutically acceptable salt or acid addition salt, preferably type I crystals, was weighed out and suspended in approximately 4.5 mL of distilled water for injection. The resulting solution was adjusted to pH 5.5-6 with 12% aqueous sodium hydroxide solution, and dissolved as the sodium salt of formula (II). The above-mentioned stabilizing additives were added, and further water for injection was added to adjust the concentration to 10 wt %. The pH was adjusted to pH 5-6, and the resulting solution was then sterile-filtered to prepare a formulation. A fixed amount of this formulation was dispensed into vials or ampoules, and freeze-dried to produce the formulation. Using this method, a solution containing 1000 mg of the sodium salt of formula (II), 334.5 mg of sodium p-toluenesulfonate, and 84.8 mg of sodium sulfate was prepared, calculated as the compound of formula (I). The active ingredient in the following examples exists as the sodium salt of formula (II), but in the tables it is converted into the compound of formula (I).

[0141] 3. Freeze-dried formulations produced using a freeze-dryer (lab machine) (1) Freeze dryers and other equipment The freeze dryer and wireless product temperature sensor used to measure product temperature were those listed in Table 2.

[0142] [Table 2]

[0143] (2) Ingredients and amounts of freeze-dried preparations The components and amounts of the components (per vial) of the freeze-dried preparation containing the sodium salt of formula (II), sodium p-toluenesulfonate, and sodium sulfate are shown in Table 3.

[0144] [Table 3]

[0145] (3) Liquid preparation method The solution was prepared by weighing out 1000 mg of the Form I crystals (calculated as the compound represented by formula (I)), placing them in a vial, suspending them in distilled water for injection, and adjusting the pH to 5.5-6 with 12% aqueous sodium hydroxide solution to dissolve the sodium salt represented by formula (II). To this solution, 900 mg of sucrose (manufactured by Merck) and 216 mg of sodium chloride (manufactured by Merck) were added, and after stirring and dissolving, distilled water for injection was added to adjust the concentration to 10 wt% as the compound represented by formula (I). The pH was adjusted to 5-6, and then sterile filtered to obtain a formulation. The formulation was filtered through a PVDF membrane filter with a pore size of 0.2 μm. 10 g of the filtrate was filled into a 14 mL transparent glass vial, partially stoppered with a rubber stopper, and loaded into a freeze dryer.

[0146] (4) Manufacturing conditions for freeze-dried preparations Among the conditions for producing freeze-dried formulations in a freeze dryer (laboratory machine), the cooling conditions are shown in Table 4, and the drying conditions are shown in Table 5. The freeze-dried formulation is produced by the following steps: 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in the freeze-dryer chamber to a predetermined cooling temperature; 2) spraying a mist into the chamber; 3) further cooling; 4) maintaining the temperature at or above the glass transition temperature; 5) primary drying; and 6) secondary drying. In Table 4, "cooling to a predetermined cooling temperature and spraying a mist" refers to steps 1 and 2, "further cooling" refers to step 3, and "maintaining the temperature at or above the glass transition temperature" refers to step 4. In Table 5, "primary drying" refers to step 5, and "secondary drying" refers to step 6. In some examples and reference examples, 4) the step of heating and maintaining the temperature at or above the glass transition temperature was not performed (in these cases, "not performed" is displayed in Table 4).

[0147] [Table 4]

[0148] [Table 5]

[0149] (Analysis method) 1)Specific surface area measurement method The specific surface area of ​​the freeze-dried preparation was measured using a specific surface area measuring device (Micromeriticis) by the Brunauer-Emmett-Teller (BET) method according to the following procedure. 1. The freeze-dried preparation was returned to room temperature in a nitrogen-purged glove box. 2. The freeze-dried preparation was loosened in a glove box, and approximately 0.5 g was roughly weighed and placed in a glass bottle. 3. The weight of the empty glass cell (including the cap) was recorded. 4. The roughly weighed freeze-dried preparation was poured into a glass cell using a funnel, the cell was capped, and the weight was recorded. 5. Pretreatment was carried out using a degassing device (Micromeriticis) at 40°C for 1 hour. 6. Nitrogen gas was introduced into the sample as an adsorbent. The equilibration interval was set to 5 seconds. After pretreatment, the sample was returned to room temperature and the weight was recorded. 7. This measurement was repeated three times.

[0150] 2) Moisture value measurement method The moisture content of the freeze-dried preparation was measured by the Karl Fischer (KF) method (volumetric titration) according to the following procedure. 1. The specimen was transferred to a weighing bottle for measuring moisture in a low humidity container (relative humidity 10% or less). 2. After measuring the weight, the specimen was added to a dehydrated solvent (a mixture of methanol and formamide (70:30)) and stirred to confirm that it was dissolved. 3. The weight of the empty weighing bottle was measured to determine the moisture content. 4. This measurement was repeated three times.

[0151] 3) Reconstitution time measurement method The reconstitution time of the freeze-dried preparation was measured visually according to the following procedure. 1. Add 10 mL of water to one vial of this product and seal with a rubber stopper. 2. Immediately after adding the water, the vial was held by fixing the top and bottom surfaces and shaken up and down to mix. 3. While visually checking for any remaining residue, the time from the start of shaking until the product was completely dissolved was recorded. 4. This measurement was repeated three times.

[0152] (Experimental results) Table 6 shows the cooling temperature and specific surface area (m 2 The mean values ​​and standard deviations of triplicate measurements of the water content (mg / g), the moisture content (%), and the reconstitution time (sec) are shown. As a result, the freeze-dried preparations of Examples 1 to 13 all had a specific surface area of ​​0.6 to 1.1 m 2 The standard deviation of the specific surface area was 0.2 m 2 The moisture content was less than the standard of 0.5% and the reconstitution time was short, less than 30 seconds, allowing dissolution in water. On the other hand, the specific surface area of ​​the freeze-dried preparation of Comparative Example 1 was 1.1 m 2 / g, and the moisture content was below the standard of 0.5%, but the reconstitution time was longer than 30 seconds. 2 / g, and the moisture content was higher than the standard of 0.5%. Therefore, taking into consideration the moisture content and reconstitution time of the freeze-dried preparation, the specific surface area of ​​the preparation of the present invention is 0.6 to 1.1 m 2 / g was found to be appropriate.

[0153] [Table 6]

[0154] 4. Freeze-dried formulations produced using a freeze-dryer (production machine) (1) Freeze dryers and other equipment The freeze dryer, ice fog system that generates ice fog, and wireless product temperature sensor that measures product temperature were used as shown in Table 7.

[0155] [Table 7]

[0156] (2) Ingredients and amounts of freeze-dried preparations The components and amounts of the components (per vial) of the freeze-dried preparation containing the sodium salt of formula (II), sodium p-toluenesulfonate, and sodium sulfate are as shown in Table 3.

[0157] (3) Liquid preparation method The solution was prepared by weighing out 1000 mg of the Form I crystals (calculated as the compound represented by formula (I)), placing them in a vial, suspending them in distilled water for injection, and adjusting the pH to 5.7-6 with 12% aqueous sodium hydroxide solution to dissolve the sodium salt represented by formula (II). To this solution, 900 mg of sucrose (manufactured by Merck) and 216 mg of sodium chloride (manufactured by Merck) were added, and after stirring and dissolving, distilled water for injection was added to adjust the concentration to 10 wt% as the compound represented by formula (I). The pH was adjusted to 5.5-6, and then sterile filtered to obtain a formulation. The formulation was filtered through a PVDF membrane filter with a pore size of 0.2 μm. 10 g of the filtrate was filled into a 14 mL clear glass vial that had been dry-heat sterilized, partially stoppered with a sterilized rubber stopper, and then loaded into a freeze dryer.

[0158] (5) Manufacturing conditions for freeze-dried preparations Among the production conditions for the lyophilized formulation, the cooling conditions are shown in Table 8, and the drying conditions are shown in Table 9. The lyophilized formulation is produced by the following steps: 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a lyophilizer chamber to a predetermined cooling temperature; 2) spraying a mist into the chamber; 3) further cooling; 4) maintaining the temperature at or above the glass transition temperature; 5) primary drying; and 6) secondary drying. In Table 8, "cooling to a predetermined cooling temperature and spraying a mist" refers to steps 1 and 2, "further cooling" refers to step 3, and "maintaining the temperature at or above the glass transition temperature" refers to step 4. In Table 9, "primary drying" refers to step 5, and "secondary drying" refers to step 6.

[0159] [Table 8]

[0160] [Table 9]

[0161] (Analysis method) The specific surface area, moisture content, and reconstitution time measurements were the same as those for freeze-dried formulations prepared using a freeze-dryer (laboratory machine).

[0162] (Experimental results) Table 10 shows the cooling temperature and specific surface area (m 2 The mean values ​​and standard deviations of triplicate measurements of the water content (mg / g), the moisture content (%), and the reconstitution time (sec) are shown. As a result, the freeze-dried preparation of Example 14 had a specific surface area of ​​0.8412 m 2 / g and 0.6~1.1m 2 The standard deviation of the specific surface area was 0.2 m 2The moisture content was 0.5% or less, which is the standard, and the reconstitution time was short, 30 seconds or less, allowing the preparation to dissolve in water. On the other hand, the specific surface area of ​​the freeze-dried preparation of Reference Example 2 was 0.6 m 2 / g, and the moisture content was higher than the standard of 0.5%. Therefore, taking into consideration the moisture content and reconstitution time of the freeze-dried preparation, the specific surface area of ​​the preparation of the present invention is 0.6 to 1.1 m 2 / g was found to be appropriate.

[0163] [Table 10]

[0164] The relationship between the specific surface area and moisture content of the freeze-dried preparation produced by the production method of the present invention is shown in Figure 1. As a result, it became clear that the moisture content tends to decrease as the specific surface area of ​​the freeze-dried preparation increases. 2 / g or more, the moisture content was 0.5% or less. [Industrial Applicability]

[0165] The production method of the present invention enables the optimization of the specific surface area of ​​a freeze-dried preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof (particularly a sodium salt), thereby enabling the control of the water content and reconstitution time in the freeze-dried preparation.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, Specific surface area: 0.6 to 1.1 m ２ / g, The reconstitution time is within 30 seconds, A method for producing a freeze-dried preparation having a water content of 0.5% or less: Step 1) cooling a solution containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a freeze-dryer chamber to a predetermined cooling temperature of −22° C. to −10° C.; Step 2) spraying a mist into the chamber; Step 3) further cooling; Step 4) heating and maintaining the mixture at a temperature equal to or higher than the glass transition temperature; and, Step 5) is a drying step; Step 2) is the step of spraying ice mist.

2. The liquid contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides, and magnesium chloride; and c) sugars and / or sugar alcohols The method for producing the freeze-dried preparation according to claim 1, wherein the liquid contains

3. The liquid contains at least the following components: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; b) sodium chloride, and, c) sucrose The method for producing a freeze-dried preparation according to claim 2, wherein the liquid contains

4. The method for producing a freeze-dried preparation according to any one of claims 1 to 3, wherein step 5) comprises a primary drying step and a secondary drying step.

5. The method for producing a freeze-dried preparation according to claim 4, wherein the time for the primary drying step (step 5) is 100 hours or less.

6. Formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein the specific surface area of ​​the freeze-dried preparation is 0.6 to 1.1 m ２ / g, the standard deviation of the specific surface area of ​​the freeze-dried preparation is 0.2 m 2 / g or less, the reconstitution time of the freeze-dried preparation is 30 seconds or less, and the water content of the freeze-dried preparation is 0.5% or less.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof Formula (II): 【Transformation 3】 The method for producing the freeze-dried preparation according to any one of claims 1 to 5, wherein the freeze-dried preparation is an amorphous sodium salt represented by the formula:

8. 7. The freeze-dried formulation according to claim 6, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is an amorphous sodium salt represented by formula (II).

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