TW200403064A - Pharmaceutical composition for injection of cefem compound - Google Patents

Abstract

A pharmaceutical composition for injection compound with high storage stability and without turbidity in the resolution, comprising: (A) a compound of the formula (I), or the pharmaceutically acceptable salt or the solvate thereof, and (B) one or the more additative selected from a group consisting of a monosaccharide, a disaccharide, a sugar alcohol and an inorganic salt.

Description

200403064 (1) Description of the invention: (1) Technical field to which the invention belongs The invention relates to a pharmaceutical composition for injection related to a phenanthrene compound. (II) Prior technology

Generally, stabilizers for injections of antiphenanthrene are known as sugars, sugar alcohols, and inorganic salts (such as sodium chloride). For example, the lyophilized preparations of phenanthrene are disclosed in JP-A-Sho 5 7-1 1 9 0 9, JP Sho 60-4 5 5 1 4 etc. There are also reports of lyophilized preparations of tertiary ammonium with 3 times the quaternary ammonium based on JP 6 3-1 7 8 2 7 and JP 4-5 9 7 3 0. Also, WO 0 0/3 260 6 describes a compound of the following formula (hereinafter referred to as compound (I)) and a salt thereof as a main drug of the composition of the present invention:

尤其 In particular, sulfate crystals are documented in PCT / JP 0 2/0 3 9 02 and also published in ICCAC (Chico, Dec. 16, 2001). # However, the review of the stabilization of compound (I) as an injection and the prevention of turbidity upon dissolution have not been reported. Compound (I) is also an effective wide-range paeonol compound against methylpenicillin-resistant Staphylococcus aureus (MR S A), especially when it is being developed as an injection. Therefore, Wangwang compound (I) has high storage stability and is not turbid when dissolved. It has high practicality for injection pharmaceutical composition, especially lyophilized preparation and spray-dried preparation. -5- 200403064 (III) Summary of the invention The present inventor developed the injection of compound (I). As a result of various analysis of its physical properties, the following information was obtained, namely: 1) The aqueous solution of the sulfate crystal of compound (I) was frozen. Drying or spray drying may change to amorphous. 2) The storage stability of the amorphous material is not high. It is easy to insolubilize, and turbidity may occur when water is re-dissolved. 3) The sulfate of compound (I) is the strong acidity of ρ Η 値 2.3 according to the general test of the Japanese Pharmacopoeia. Therefore, it must be adjusted to the physiological ρΗ that is possible for injection administration in vivo, that is, weakly acidic ~ neutral. However, lyophilized preparations adjusted with base PΗ alone to be neutral near redissolution are more unstable and turbid than the single-drug formulation. Therefore, to develop the compound ⑴ into an amorphous form by injection, it is necessary to work on the preparation. As a result of further review, it was found that the combination of monosaccharides, disaccharides, sugar alcohols, inorganic salts, and the like as additives can eliminate the above disadvantages and complete the following invention.

(1) S3 € & injectable pharmaceutical composition featuring the following components (A) and (B): (Α) ϊζ k compound (1), its pharmacological tolerance, or these solvates

(B) An additive selected from 1 or more of monosaccharides, disaccharides, sugar alcohols and inorganic salts. -6- 200403064 (2) The pharmaceutical composition described in the above (1), wherein the component (A) is a sulfate salt of the compound (I) or a solvate thereof. (3) The pharmaceutical composition according to the above (2), wherein the component (A) is a non-crystalline sulfate or a solvate of the compound (I). (4) The component (B) is selected from glucose, maltose, mannitol and sodium chloride! The pharmaceutical composition according to any one of (1) to (3) above as an additive. (5) The pharmaceutical composition according to the above (4), wherein the component (B) is sodium chloride. (6) The content of sodium chloride is 1-3 molar equivalents to the component (A) of the pharmaceutical composition according to the above (5). (7) The pharmaceutical composition described in any one of (1) to (6) above with a component (C) and a pH adjusting agent. (8) The pharmaceutical composition according to the above (7), wherein the pH adjusting agent is sodium hydroxide or a basic amino acid. (9) Compound (A) a sulfate or a solvate of the compound (I), (B) sodium chloride, and (C) sodium hydroxide or a basic amino acid as a p Η adjuster as described above (1 ) The medicinal composition described. U〇) The pharmaceutical composition according to the above (9) or (100), wherein the content of the component (A) and sodium chloride is 1 to 3 mol equivalents. 〇1) The pharmaceutical composition according to (9) or (100), in which the content of the component (A) and the pH adjusting agent is 1 to 1.5 mol equivalents. U 2) The pharmaceutical composition according to any one of the above (1) to (1 1), which is a lyophilized preparation. (1 3) The pharmaceutical 200403064 composition according to any one of (1) to (1 1) above, which is a spray-dried preparation. (1 4) The pharmaceutical composition according to the above (1 2) or (13) at 50 t: the residual ratio of the component (A) after one week of storage is 70% or more before storage. (15) The medicinal composition according to the above (14) with a survival rate of 75% or more before storage. (16) The medicinal composition according to (14) above, wherein the remaining rate is 80% or more before storage. (1 7) After storage at 50 ° C for 1 week, the turbidity of the component (A) at a concentration of 5 mg (force value) / g when the infusion for injection was dissolved was 1.60 nm. The pharmaceutical composition according to any one of (1 2) to (16) below 0. (18) The pharmaceutical composition according to the above (17), having a turbidity of 600 nm or less at 0.6 nm or less. (19) The medicinal composition according to the above (17), having a turbidity of O.D. 600 nm of 0.05 or less. (20) The medicinal composition according to the above (17), having a turbidity of 0.6 to 600 nm and 0.02 or less. (21) Compound (A) a sulfate or a solvate of the compound (I), (B) sodium chloride, and (C) sodium hydroxide or a basic amino acid as a p Η modifier, to the component ( A) The content of sodium chloride is 1 to 3 mol equivalents, the content of the PQ regulator is 1 to 1.5 mol equivalents, and the residual rate of the component (A) after storage at 50 ° C for 1 week is as before 70% or more, and the turbidity of the component (A) at a concentration of 5 mg (force value) / g after dissolution during injection for infusion for injection is in a range of 0. D. 600 nm, and 1.0 or less, as described in (1) above. Pharmaceutical composition. (22) The residual ratio of the component (A) is 80% or more before storage, and the turbidity is > 8-200403064 O.D. 600 nm, and the pharmaceutical composition according to the above (21), which is 0.05 or less. (2 3) A method for producing an injectable pharmaceutical composition comprising a process of dehydrating an aqueous solution containing the following ingredients (A) and (B): (A) The compound (I) according to the above (1), a pharmacologically acceptable salt thereof, or these A solvate, and (B) one or more additives selected from monosaccharides, disaccharides, sugar alcohols, and inorganic salts. (24) The aqueous solution further contains the manufacturing method described in the above (23) as the pH adjusting agent of the component (C). (25) The aqueous solution contains the compound (I) as a component (A), a sulfate salt or a solvate of these, sodium chloride as a component (B), and sodium hydroxide or a basic amine as a component (C) The production method according to the above (23) of the base acid. (2 6) A lyophilized preparation or a spray-dried preparation of the compound (I) obtained by the production method described in any one of (23) to (25) above. (IV) Embodiment The component (A) of the main drug of the injectable pharmaceutical composition (hereinafter referred to as the present composition) of the present invention is the aforementioned compound (I), a pharmacologically acceptable salt thereof described in WO 00/32606, or the like The solvate is useful as an antibacterial agent. The pharmacologically acceptable salt may be a salt or an intramolecular salt formed from an inorganic base, ammonia, an organic base, an inorganic acid, an organic acid, an authentic amino acid, a halogen ion, or the like. The inorganic test can be a metal test (Na, K, etc.), a soil test metal (Mg, etc.), and the organic test can be procaine, 2-phenethylprecipylamine, diethylethylenediamine, ethanolamine, diethanolamine , Reference hydroxymethylaminomethane, polyhydroxyalkylamine, N-methylglucosamine and so on. The inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like. There are -9-200403064 organic acids can be p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid and so on. The basic amino acid may be lysine, L-alginic acid, ornithine, histidine, and the like. The solvate may be a hydrate (for example, a monohydrate, a dihydrate, a trihydrate, a tetrahydrate, a pentahydrate, a 6hydrate, a 7hydrate, etc.) and an alcoholate. The component (A) is preferably a sulfate (for example, 0.5 sulfate, 1 sulfate) of the compound (I) or a hydrate thereof. Particularly preferred is 1 sulfate or a hydrate (eg, 1, 2, 3, 4, 5 hydrate, etc.). The monosulfate of the compound (I) is preferably crystallized from the viewpoint of storage stability. However, the crystal may be converted to amorphous in preparation processes such as lyophilization and spray drying, and the preparation process and subsequent storage may be decomposed to reduce the price. In this case, a decomposed product derived from the side chain at the 3-position or a Δ2 body of the compound (I) may be mixed. When the water was re-dissolved, the turbidity of the polymer such as the compound (1) was presumed. However, this composition has no compound (1) crystallized, and the above-mentioned disadvantages are eliminated, so it is extremely useful when used as an injection. Ingredient (B) is used as a stabilizer in order to suppress decomposition during preparation or storage of ingredient (A). It also has the effect of suppressing or reducing turbidity when the component (A) is dissolved in an infusion solution for injection (for example, physiological saline, glucose solution) and the like. The prevention effect of turbidity is presumed to be due to the generation of a polymer (for example, a 2-volume body and a 3-volume body) due to the inhibitory component (A). Ingredient (B) is one or more additives selected from monosaccharides, disaccharides, sugar alcohols and inorganic salts. Monosaccharides may be glucose, mannose, galactose, fructose, etc., and grape bran is preferred. Disaccharides can be maltose, sucrose, lactose, fructose, cocoon honey, xylose 200403064 alcohol, etc., maltose is preferred. The sugar alcohol may be D-mannitol, sorbitol, glycerol, inositol, etc., and D-mannitol is preferred. The inorganic salt may be sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and sodium chloride is preferred. Ingredient (B) is preferably an inorganic salt, especially sodium chloride. The content of ingredient (B) to ingredient (A) is usually about 0.1 to 5 mole equivalents, preferably about 0.5 to 3 mole equivalents, especially about 1 to 3 mole equivalents, more preferably about 1.5 to 2.5 moles. equivalent. In particular, when sodium chloride is used, the larger the content, the more stable the component (A), and the turbidity when water is dissolved is also suppressed. Especially when sodium chloride content is used at 2 mole equivalents, turbidity is suppressed by about 10% to 2% when used at 1 mole equivalent. However, the suppression effect of turbidity reaches a certain level at a content of 2 mol equivalent of sodium chloride, and when it is added above, the appearance of the lyophilized preparation may be partially broken. Therefore, one suitable aspect is that the content of sodium chloride to the component (A) is about 1 to 3 mole equivalents, more preferably about 1.5 to 2.5 mole equivalents, and particularly preferably about 2 mole equivalents. The above-mentioned suitable content range of the component (B) is to adjust the composition to 100 ~ 200 mg (power value) / g according to the component (A) when the water is dissolved to adjust the pH to 3 ~ 7, preferably a weak acid of PH4 ~ 7 to near neutral Timely. Or the composition is adjusted to ρ Η 3 ~ 7, preferably ρ Η 3.5 ~ 6, especially 4 ~ 6 when the physiological salt solution is dissolved according to the component (A) 5 mg (force value) / g. In addition, when component (B) is used with sodium chloride and maltose, the stabilization effect is improved. The composition may further contain (C) a pH adjuster. The pH adjusting agent can be used to adjust the composition to a physiological pH (for example, PH 3 to 7) used as an injection, such as an alkali metal hydroxide (such as sodium hydroxide), an alkali metal carbonate 200403064 salt (such as sodium carbonate). , Sodium bicarbonate), basic amino acids (such as lysine, L_alginine, ornithine, histidine). Sodium hydroxide and L-alginic acid are preferred. The content of the pH adjusting agent is usually an amount of P Η 3 to 7 when the pharmaceutical composition of the present invention is dissolved in an infusion solution for injection. For example, the composition is adjusted to ρ Η 5 to 7, preferably ρ Η 6 to 7, near neutral according to the component (A) 1 0 0 ~ 2 0 0 m g (force value) / g when water is dissolved. Or the composition is adjusted to pH 3 ~ 7, preferably pH 3.5 ~ 6, especially 4 ~ 6 when the physiological salt solution is dissolved according to the component (A) 5 mg (force value) / g. In these cases, the content of sodium hydroxide is about 1.0 · ~~ !! 5 mole equivalents to the component (A), preferably about 1.1 ~ 1.3 mole equivalents. For L-alginic acid is about; [.〇 ~ 1.5 mol equivalent, preferably about 1.1 ~ 1.2 mol equivalent. The acid addition salt of compound (I) is highly acidic in a single dose (for example, 1 sulfate is pH 2.3), so when used as an injection, it must be adjusted to the above-mentioned physiological ρΗ, only with (C) ρ Η adjusted Agent, the stability is reduced, and significant turbidity occurs when redissolved. However, in combination with the aforementioned (B) component, these discomforts can be prevented. That is, one of the characteristics of this composition is to consider its practicality as an injection, and it is desirable to optimize the content of these ingredients (A), (B), and the desired ingredient (C). In addition, when the pH adjusting agent is used as an additional dissolving solution in clinical preparations, it is necessary to examine the necessity of not corroding the glass of the sterile container, and troublesome and poor usability during dissolution. However, if a pH adjuster is used in the present composition, such an inconvenience can be avoided. Therefore, this composition should preferably contain the above-mentioned components (A), (B) and (C). At this time, (B) is preferably sodium chloride, and the content of sodium chloride is particularly preferably 1 to 3 mole equivalents to the component (A), preferably approximately 1.5 to 2.5 mole equivalents. More preferably, the content of the pH adjusting agent is the above physiological pH when the composition is dissolved in an infusion solution for injection. For example, the composition is prepared according to the component (A) 1 0 0 ~ 2 0 0 mg (power value) / g in water. When dissolving, 200403064 is set to pH 5 ~ 7, preferably pH 6 ~ 7, and particularly suitable pH adjuster is sodium hydroxide and L-alginic acid. The shape of the composition is not necessarily limited, and it is preferably a powder preparation such as a lyophilized preparation and a spray-dried preparation, and is preferably filled in a vial. It is particularly preferred that these are sterile and ensure that they are pyrogen-free. This composition improves the stability in the formulation process or the subsequent storage as follows, and suppresses or reduces the turbidity when the infusion for injection is dissolved. For example, the composition (A) can be stored in a vial at 50 ° C for K weeks, and the residual rate of the component (A) is 70% or more, preferably 75% or more, and more preferably 80% or more before storage. After the composition is stored at 50 ° C in a vial for 1 week, the turbidity of the component (A) is, for example, 5 mg (force value) / g when dissolved in an infusion solution for injection (preferably physiological saline) is 0D ·: 6 0 0 nm is 1.0 or less, preferably 0.5 or less, more preferably 0 · 1 or less, more preferably 0.05 or less, and even more preferably 0.02 or 0.01 or less. It is particularly preferred that the composition is compounded with (A) the sulfate of the compound (I) or a solvate thereof, (B) sodium chloride, and (C) a pH adjuster (such as sodium hydroxide). (A) is about 1 to 3 mole equivalents, the content of the pH adjuster is about 1.0 to 1.5 mole equivalents, and the residual ratio of the component (A) before 5 (TC storage for 1 week) is as before More than 70%, preferably more than 75%, especially more than 80%, and the turbidity when the component (A) is 5 mg (force value) / g when the infusion for injection is dissolved is 0D .: 6 0 0 nm is 1.0 Below, preferably 0.5 or less, particularly 0.1 or less, more preferably 0.05 or less, and more preferably 0.02 or 0.01 or less. Stabilization of the preparation and suppression of turbidity can be adjusted by the types and contents of the aforementioned additives and P Ρ regulators 200403064 This composition can be produced by mixing the aforementioned ingredients (A) and (B) and the desired ingredient (C). It is particularly preferable to mix the aforementioned ingredients (A) and (B) and the desired ingredient ( C) After preparing the mixed aqueous solution, 'this is lyophilized, spray-dried, and other dehydration processes and manufactured. The composition obtained has no particular problem with the shape of compound (I)' depending on the ingredients The types and contents of B) and (C) are in various forms, and can take any shape such as free body, acid addition salt (such as sulfate), alkali metal salt, amino acid addition salt, or a mixture of these. When the water is re-dissolved, the compound (I) is free to swim, and the intended injection can be obtained. When the component (C) is also mixed, the lyophilized preparation and the spray-dried preparation mixed with the component (A) and (B) can also be prepared Then, (C) uses powder as a two-layer filling or a combination with an additive solution, and this form is also within the scope of the present invention. The suitable production of the composition is as follows. (Freeze-dried preparation) The component (A) will be contained ~ (C) A predetermined concentration (for example, component (A) of 100-200 mg / g), prepared by PH (3 ~ 7, preferably 5 ~ 6), filtered, and after dispensing in a vial, -2 0 ~ -5 0 ° C, preferably -3 0 ~ -4 0 ° C, freezing for several hours, preferably 2 ~ 5 hours (freezing). Once at -20 ~ 10 ° C, preferably 0 ~ 5 ° C, 2 ~ 50Pa It should be vacuum dried for 5 ~ 2 0 Pa for several hours to several tens of hours, preferably 20 ~ 30 hours (one time drying). Following 10 ~ 50 ° C, preferably 20 ~ 3 (TC, 1 ~ 50Pa, preferably 1 ~ 3 Pa vacuum drying Hours to tens of hours, preferably 1 to 5 hours (secondary drying). After lyophilization is completed, the container is replaced with dry nitrogen and sealed. (Spray Drying) Concentrations (A) to (C) (A) Aqueous solution of 150 ~ 500 mg / mg), p Η (2 ~ 7, preferably 4 ~ 7), after preparation, filter and spray dry -14-200403064. Temperature setting of spray dryer With I η 1 50 ~ 2 0 0 ° C, preferably 18 0 ~ 2 0 0 ° C 'Out 90 ~ 140 ° C' preferably 2 ~ 13. 〇Execution. As long as it is within this range, the component (A) is not easily thermally decomposed, and the amount of water is suitably reduced. Because the component (A) m is more hygroscopic than S, in order to prevent re-hygroscopicity, the trapping bottle should be warmed (35 ~ 90 ° C, preferably 50 ~ 7 (rc). After spray drying, the obtained The powder is dispensed into a vial. The other method is to use the ingredients (A) and (B) to imitate the spray drying described above, and the obtained powder is dispensed into a vial and filled with the ingredient (C). Xin The present invention further provides the injection obtained by the above method. The pharmaceutical composition (such as a lyophilized preparation, a spray-dried preparation, and an injection using these) is preferably used. The pharmaceutical composition for injection of the present invention is preferably dissolved in an infusion solution for injection (such as a physiological saline solution and a glucose solution), and administered by intravenous drip injection and muscle. The form of the injection is used as an antibacterial agent. For example, in the form of an intravenous drip injection, the component (A) is about 1 to 20 mg (force value) / g with compound (I), preferably about 5 to 10 mg (force value ) / G, in the form of intramuscular injection, it is about 50 ~ 50 0 (force value) / g, preferably about 100 ~ 3 3 0 (force value) / g. It is prepared when used. Φ The present invention uses the composition Characteristics, provide manufacturing methods of antibacterial agents, and prevent and treat various infections. At this time Compound (I) can be administered to humans at, for example, about 0.1 to 100 mg / kg / day, preferably about 0.5 to 50 mg / kg / day, and divided into two to four times a day as desired. The component (A) of the example is the 1 sulfate aqueous crystal (2 or 3 hydrate) of the compound (I) (hereinafter referred to as the compound S). The amount of the additive is -15-200403064 to the compound S. (Stability test) The determination of the potency of the compound S and the decomposition products were performed by liquid chromatography under the following conditions. Column YMC-Pack ODS-AM AM-302, S-5pm, 12nn Solvent IJ 0.1% TFA (trifluoroethyl Acid ester) 1 / acetonitrile = 92/8 development speed 1.0 m L / mi η injection volume 1 Ομί detection wavelength 2 9 5 η m column temperature 2 5 ° C sample temperature (turbidity)

The turbidity was evaluated as 0 D · (absorbance) 6 0 0 ΙΠ 値 when the lyophilized preparation or spray-dried preparation was compound S at 5 mg (force value) / m g when it was re-dissolved in physiological saline. The P Η of the solution at this time is in the range of p Η 3 to 4 at all times. Measuring machine BECKMAN DU7400 spectrophotometer

Measurement conditions Cell temperature 25 ° C Test example 1 (Preparation of lyophilized preparation) After preparing a predetermined concentration (compound S100 ~ 200mg (power value) / g of compound S) of various additives, 10 g of an aqueous solution of compound S of a predetermined p Η, Record p Η and sterilize with Stei'ibecksGV (0.22gm: MILLIP0RE) (Note: p Η in the table below indicates the ρ η when the solution is prepared). After filtering, dispense to ice storage (5 ° C) ) Storage. The filtered solution is dispensed in a 5 ml vial (B V K-16 200403064 3vUl) as 100 mg (force) of compound S per vial. After dispensing, the rubber stopper is half-sealed and plugged under the following conditions It was lyophilized. After lyophilization, the library was replaced with nitrogen to seal the plug. Immediately after removal, the accelerated test was performed at 5 ° C (1 week) to investigate the stability and turbidity during re-dissolution. Force price is' 10 0% ° (freeze-drying) Machine used: Republic freeze-dryer RL-60BS (manufactured by Kyowa Vacuum Co., Ltd.) Setting 値: Time shed temperature vacuum degree storage 1 00C-2 hours or more 20 hours or more Freeze more than 2 hours-4 ° C-primary drying 〇t 1 〇P a secondary drying Re-pressurize at 25 ° C 2Pa with dry nitrogen, and tie in the warehouse.

200403064 (Table i) Example 1 — ~ — _ Additive test item storage conditions PH 5 0 ° C 1 W power value 8 0.9% Comparative Example 1 1.69 precipitation of solution appearance ---- turbidity 0.1392 Example 1 glucose power value 8 7.6% 2 0 w / w% 1.66 Solution appearance transparency turbidity 0.0022 Example 2 Maltose power value 8 7.8% 2 0 w / w% 1.7 1 Solution appearance transparency--------- Turbidity 0.0005 Example 3 D-mannitol power value 7 9.6% 20 w / w% 1,70 solution appearance transparency turbidity 0.0007 NaCl power value 9 4.1% Example 4 1 7 w / w% 1.66 solution appearance transparency --- ( 2.〇mole equivalent) Turbidity 0.0016

(100 m g (force value) / g system | j) Compound S is stabilized due to the addition of additives. In addition, the turbidity of the re-dissolved solution in which the compound s was dissolved in physiological saline at 5 mg (valence) / g was also reduced. In addition, the C 3 side chain formed from the imidazopyridine skeleton from which the main decomposed compound S identified outside the turbid substance was removed, and the HPLC peak area derived from the △ 2 body of the compound S were also suppressed. Especially when sodium chloride was added to the preparation, no decomposition products were observed on HPLC, and a high stabilization effect was seen. 18 200403064 Test Example 2 A lyophilized preparation was prepared in accordance with Test Example 1. The stability and turbidity at the time of re-dissolution were investigated. Because compound S is strongly acidic according to the general test method of the Japanese Pharmacopoeia, pH 値 is 2.3, and it must be adjusted to a physiologically acceptable pH when administered in vivo. Therefore, the sodium hydroxide aqueous solution is adjusted to a pH suitable for injection. (Table 2) Preservative conditions for reference examples Additive storage conditions pH adjuster pH 5 0 ° C 1 W Reference examples 1-1.54 Power value 7 9.0% Solution appearance turbidity 0.1225 Reference example 2 NaOH 5.57 Power value 6 5.4% Solution appearance turbidity Turbidity 1.0776 Reference Example 3 NaOH 6.08 Power value 6 3.7% Appearance turbidity turbidity 1.1004 Reference Example 4 NaOH 6.78 Power value 6 5.2% Solution appearance turbidity 1.0241 (100 mg (power value) / g preparation) Visible adjustment to PH5 Preparations around ~ 7 have lower potency than single taste. And the occurrence of turbidity also increased significantly. These tendencies are made more pronounced by acceleration. Test Example 3 A lyophilized preparation was prepared following Test Example 1, and the content of sodium chloride was changed for review. 200403064 (Table 3) Example Additive Test item Storage conditions NaCl pH adjuster pH 5 0 ° C 1 W Comparative example 2-NaOH 6.83 Force value 6 6.4% Solution appearance turbidity turbidity 1.0931 Example 5 0.5 Molar equivalent NaOH 6.42 force Value 7 3.8% solution appearance turbidity 0.5827 Example 6 1. 〇 Moral NaOH 6.6 1 force value 7 7.1% solution appearance turbidity 0.3490 Example 7 2.0 Molar equivalent NaOH 6.51 force value 8 4.5% solution appearance Transparent turbidity 0.0068 (1 0 0 mg (force value) / g system lj)

It can be seen that with the increase of the amount of sodium chloride, the stability of the force is stable. Moreover, the turbidity decreased significantly with the increase of the amount of sodium chloride added, and the turbidity was almost suppressed by the addition of 2.0 mol equivalent. The decomposition products also decrease with the increase of sodium chloride. Test Example 4 A lyophilized preparation was prepared following Test Example 1, and a comparison was made between a compound S in which sodium chloride was added at 2.0 mol equivalents and 3.0 mol equivalents. 20 200403064 (Table 4) Storage conditions of the additives throughout the examples NaCl pH adjuster pH g Test item 5 0 ° C 1 W 2.0 Molar equivalent Power value 7 6.7% Example 8 NaOH 5.48 Solution appearance turbidity 0.0108 3.0 Molar Equivalent power value 7 8.7% Example 9 NaOH 5.81 solution appearance transparent turbidity 0.0 110 (200 mg (power value) / g preparation) It can be seen that when sodium chloride is added at 2.0 mol equivalent and 3.0 mol equivalent is added No stability differences. Test Example 5 A lyophilized preparation was prepared following Test Example 1 and the effect of pH was investigated. (Table 5) Preservative Additive Test Item Storage Conditions NaCl pH Adjuster pH 5 0 ° C 1 W Example 10 2.0 Molar Equivalent NaOH 4.5 Force Value 8 1.1% Solution Appearance Transparent Turbidity 0.0125 Example 8 2.0 Molar Equivalent NaOH 5.48 Force value 7 6.7% Appearance transparent turbidity 0.0108 Example 1 1 2.0 Molar equivalent NaOH 6.44 Force value 7 5.3% Solution appearance turbidity 0.0082 (2 0 0 mg (force value) / g system) 21 200403064 It can be seen that the pH will decrease when the pH is near neutral. Test Example 6 A lyophilized preparation was prepared following Test Example 1 and the effect of adding maltose was investigated. (Table 6) Examples Additives Test items Storage conditions NaCl Sugar pH adjustment Neat! J pH 5 0 ° C 1 W Example 1 1 2.0 Molar equivalent-NaOH 6.44 Power value 7 5.3% Turbidity of solution appearance 0.0082 Example 1 2 2.0 Molar equivalent Maltose 2 0 w / w% NaOH 6.44 Power value 7 9.1% solution appearance turbidity 0.0083 (200 mg (force value) / g preparation) It can be seen that the power value is more stable due to the addition of maltose, and the decomposition products are also reduced. Test Example 7 L-alginic acid was used as a pH adjusting agent, and a lyophilized preparation was prepared following Test Example 1.

200403064 (Table 7) Example Additive Storage Conditions NaCl pH Adjuster pH g Formula Test Item 5 0 ° C 1 W Example 13-L-Ar g 6.88 Power Value 7 8.4% Solution Appearance Transparent Turbidity 0.0229 Example 14 0.5 Mo Ear equivalent L-Ar g 6.54 Force value 8 1.5% solution appearance transparent turbidity 0.0018 Example 15 1.0 Molar equivalent L-Ar g 6.54 Force value 8 2.4% solution appearance transparency turbidity 0.0032 Example 16 2.0 Moire equivalent L- A rg 6.50 force value 8 4.6% solution appearance turbidity 0.0028 (100 mg (force value) / g preparation) It can be seen that the strength value is stable as the amount of sodium chloride increases. The turbidity was substantially suppressed by adding more than 0.5 mol equivalent of sodium chloride. · Test Example 8 (Preparation of spray-dried preparations) After preparing a predetermined concentration of various additives (50 to 500 mg (potency) / mg of compound S1) and an aqueous solution of compound S of predetermined p Η, record the pH and use SteribecksGV (0.22pn: manufactured by Millipore) Sterile filtration (Note: p Η in the table below is P Η when the sample is redissolved at -20 ° C and stored at 1 W). The liquid after spraying was spray-dried under the following conditions. After spray-drying, in a low-humidity nitrogen environment (in a drying box), aliquot a 20 mg vial (B V κ-2 0 ν ia 1) -23- 200403064 into 100 mg (force value) powder. An accelerated test (1 week) was performed at 50 ° C to investigate storage stability and turbidity upon redissolution. (Spray Drying) Equipment used: Spray Dryer Spray Dryer-SD-100 (Tokyo Physicochemical Machinery Co., Ltd.)

2.0 m L / mi η 200 ° C Setting 値: liquid feed inlet temperature outlet temperature dry air volume spray pressure trap bottle (Table 8) 1 2 0 ～ 1 3 0 〇C 0.60 ～ 0.65m3 / mi 50kPa heating ( 6 0 ° C) Example Additive Test Item Storage Conditions PH 5 0 ° C 1 W Comparative Examples 3-2.33 Power Value 6 6.2% Precipitation Turbidity of Solution 0.3285 Example 1 7 Maltose 2 0 w / w% 2.3 5 Power Value 9 2.5% solution appearance transparent turbidity 0.0141 Example 1 8 mannitol 20 w / w% 2.37 power value 7 0.4% solution appearance transparency turbidity 0.0141 Example 1 9 NaCl 2.0 Molar equivalent 2.3 1 power value 8 9.1% Solution appearance turbidity 0.0446 (100 mg (force value) / via 1 small preparation) -24- 200403064 Compound s is stabilized due to the addition of additives. In addition, the turbidity of the redissolved solution in which the compound s was dissolved in physiological saline at 5 mg (force value) / g was also reduced. In addition, the C3 side chain formed from the imidazopyridine skeleton from which the main decomposed compound S identified outside of the turbid substance was removed, and the peak area of ΗPLC derived from the Δ2 body of the compound S were also suppressed. Especially in the addition of maltose preparations, those without turbidity and high stability can be obtained. Test Example 9 A spray-dried preparation was prepared following Test Example 8, and the stability of storage and the turbidity of re-dissolution were investigated. Since compound S is strongly acidic according to ρΗ 値 2.3 of the general test method of the Japanese Pharmacopoeia, it must be adjusted to p 静脉 which is physiologically possible for intravenous administration. Therefore, for the formulation of Test Example 8 with an increase in turbidity and stabilization effect of 2 Q% maltose, the sodium hydroxide aqueous solution was adjusted to ρ 适合 suitable for injection. (Table 9) Example Additive Storage conditions Maltose pH adjuster pH Test item 50 0 ° C 1 W Comparative example 4 2 0 w / w%-2.35 Power value 9 2.5% Solution appearance turbidity 0.0141 Example 20 2 0 w / w% NaOH 4.50 power value 7 4.9% solution appearance transparent turbidity 0.0025 Example 2 1 2 0 w / w% NaOH 7.0 1 power value 7 7.2% solution appearance transparency turbidity 0.0051 (1 OOmg (power value) / vial small Partial formulation) 200403064 It can be seen that the formulation is adjusted to a pH of around 4 to 7, and the power value is lower than that of an unadjusted product. The occurrence of turbidity can be suppressed by pH adjustment. Test Example 1 The addition of 2.0 molar equivalents of sodium chloride also neutralized the pH and examined the effect of suppressing turbidity. (Table 10) Example Additive Storage Conditions NaCl pH adjuster pH Test item 50 0 ° C 1 W Comparative Example 5 2.0 Molar equivalent-2.31 Power value 8 9.1% Solution appearance turbidity 0.0446 Example 22 2.0 Molar equivalent NaOH 7.10 Power value 8 4.7% solution appearance turbidity -0.0017 (100 mg (power value) / Via 1 small fraction) It can be seen that it can be adjusted by neutralizing P Η, and sodium chloride can also be added to suppress turbidity. Test Example 1 1 A spray-dried preparation was prepared following Test Example 8, and the content of sodium chloride was changed to check storage stability and turbidity during redissolution. 26 200403064 (Table 1 l) Examples of additive test items Storage conditions Maltose NaCl pH 5 0 ° C 1 W Force value 9 2.5% Comparative example 6 2 0 w / w%-2.35 Solution appearance turbidity 0.0141 1.0 mole Equivalent power value 9 3.5% Example 23 2 0 w / w% 2.50 Solution appearance transparent turbidity-0.0008 2.0 Molar equivalent power value 9 6.8% Example 24 2 0 w / w% 2.33 Solution appearance transparent turbidity 0.0015 3.0 Mo Ear-equivalent power value 9 3.4% Example 25 2 0 w / w% 2.3 1 Solution appearance transparent turbidity 0.002 1 (100 mg (power value) / vial system)} () It can be seen that the combination of maltose and sodium chloride can make It is stable and stable. Especially when 2.0 mol equivalent is added, it shows high stability. The turbidity is not reduced by maltose alone, and it is reduced by adding sodium chloride. The addition of 1.0 mol equivalent of sodium chloride can be roughly suppressed. Test Example 1 2 Test Example 8 A spray-dried preparation was prepared, and L_alginic acid was used as the pH adjuster, and a pH adjustment test was performed when the comparative solution was prepared, and two layers were filled with the pH adjuster. 200403064 (Table 12) Example Additive Test Item Storage Conditions NaCl Maltose p H adjuster pH 50 ° C 1W Comparative Example 7 2.0 Molar equivalent 20 w / w%-2.33 quot value 96.8% Solution appearance turbidity 0.0015 Example 26 2.0 Molar equivalent 20 w / w% L-Arg 5.19 Force value 93.7% solution appearance turbidity-0.0008 Example 27 2.0 Molar equivalent 20 w / w% L-Arg two-layer charge 6.98 Force value 95.1% solution appearance transparent turbidity 0.0039 Comparative Example 8 3.0 mole equivalent 2 0 w / w%-2.3 1 force value 93.4% solution appearance transparent turbidity 0.0021 Example 28 3.0 mol equivalent 20 0 w / w% L-Arg 3.66 force value 94.7% solution appearance transparency turbidity __ 0.0029 Example 29 3.0 Molar equivalent 20 w / w% L-Arg two-layer charge 3.77 force value 96.9% solution appearance transparent _ turbidity 0.0029 (100 mg (power value) / via 1 small fraction preparation) industrial use possible The present invention provides a pharmaceutical composition for injection, which has high storage stability of the compound (I) and has high practicality without turbidity upon re-dissolution. (V) Schematic description: None 28

Claims (1)

200403064 Patent application scope: 1. A pharmaceutical composition for injection, characterized by compounding the following components (A) and (B): (A) compound of formula (I), its pharmacological tolerance, or solvates of these (B) an additive selected from the group consisting of monosaccharides, disaccharides, sugar alcohols, and inorganic salts} or more. 2. The pharmaceutical composition according to item 丨 of the application, wherein the component (A) is a sulfate or a solvate of the compound (I). 3. The pharmaceutical composition according to item 2 of the patent application, wherein the component (A) is a non-crystalline sulfate or a solvate of the compound (I). 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the component (B) is an additive selected from glucose, maltose, mannitol and sodium chloride 1 or more. Φ 5. The pharmaceutical composition according to item 4 of the patent application scope, wherein component (b) is sodium chloride. 6. The pharmaceutical composition according to item 5 of the scope of patent application, wherein the content of sodium chloride is 1-3 molar equivalents to the component (A). 7. The pharmaceutical composition according to any one of items 1 to 6 of the scope of application for a patent, wherein the component (C) is further compounded as a pΗ adjusting agent. 8. The pharmaceutical composition according to item 7 of the patent application scope, wherein the pH adjusting agent is 29 200403064 sodium hydroxide or a basic amino acid. _ 9 · The pharmaceutical composition according to item 1 of the scope of patent application, wherein (A) the sulfate of the compound (I) or a solvate thereof, (B) sodium chloride, and (C) hydrogen as a pH adjusting agent Sodium oxide or basic amino acid. 10 · The pharmaceutical composition according to item 9 of the scope of patent application, wherein the content of the component (A) and sodium chloride is 1 to 3 molar equivalents. 1 1 · The pharmaceutical composition according to item 9 or 10 of the scope of patent application, wherein the content of the component (A) and the pH adjusting agent is 1 to 1.5 mol equivalents. 1 2 · The pharmaceutical composition according to any one of claims 1 to 11 in the scope of patent application, which is a lyophilized preparation. 1 3. The pharmaceutical composition according to any one of claims 1 to 11 of the scope of patent application, which is a spray-dried preparation. 1 4. If the pharmaceutical composition of item 12 or 13 of the scope of patent application, the residual rate of the component (A) after storage at 50 ° C for 1 week is more than 70% before storage. 15. If the pharmaceutical composition of item 14 in the scope of patent application, the residual rate is more than 75% before preservation. 16. If the pharmaceutical composition of item 14 in the scope of patent application, the residual rate is more than 80% before preservation. 17. The pharmaceutical composition according to any one of claims 12 to 16 in the scope of patent application, wherein after stored at 50 ° C for 1 week, the concentration of component (A) is 5 mg (force value) / g for injection. The turbidity when the infusion solution was dissolved was OD · 600 nm 値 1.0 or less. 18. The pharmaceutical composition according to item 17 of the scope of patent application, wherein the turbidity is 0.6 D. 600 nm or less. 19. The pharmaceutical composition according to item 17 of the scope of patent application, wherein the turbidity is -30- 200403064 0. D. 600 n m 値 is 0.0 5 or less. 2 〇 • The pharmaceutical composition according to item 7 in the scope of patent application, wherein the turbidity is 0. D. 600 n m 値 is 0.0 2 or less. 2 1 · The pharmaceutical composition according to item 1 of the scope of patent application, wherein (A) the sulfate of the compound (I) or a solvate thereof, (B) sodium chloride, and (C) hydrogen as a pH adjusting agent Sodium oxide or basic amino acid, the content of sodium chloride in the component (A) is 1 to 3 mole equivalents, the content of the pH adjuster is 1 to 1.5 mole equivalents, and the ingredients are stored at 50 ° C for 1 week D. 6 0 The residual rate of (A) is more than 70% before storage, and the turbidity of the component (A) after the storage is 5 mg (force value) / g concentration when the infusion for injection is dissolved is 0.60. 0 nm 値 is 1.0 or less. 22. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the residual rate of the component (A) is 80% or more before storage, and the turbidity is not more than 0.05 at 0.005. 2 3. — A method for manufacturing a pharmaceutical composition for injection, comprising dehydrating an aqueous solution containing the following components (A) and (B): (A) If the compound (I) described in item 1 of the patent application scope, its pharmacology Allowable salts or solvates of these, and (B) additives selected from monosaccharides, disaccharides, sugar alcohols, and inorganic salts, or more. 24. The manufacturing method according to item 23 of the scope of patent application, wherein the aqueous solution further contains a PΗ adjusting agent as a component (C). 25. The manufacturing method according to item 23 of the scope of patent application, wherein the aqueous solution contains the compound (I), its sulfate, or a solvate of these as the component (A), sodium chloride as the component (B), and Sodium hydroxide or basic 200403064 amino acid as component (C). 26. — A lyophilized preparation or a spray-dried preparation of the compound (I) obtained by the manufacturing method according to any one of claims 2 to 25. -32- 200403064 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the element representative symbols in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 3 200403064 Explained matters: This case is in accordance with Article 20, Paragraph 1 of the Patent Law □ Paragraph 1 of the Paragraph or Paragraph 2 of the Paragraph, and its date is: year, month, and year. ◎ Prior to the application of this case, the following countries (regions) have been applied for patent 0 claiming international priority: [format please follow: receiving country (region); application date; application note number sequence notes] 1. Japan 2002.06.21 Special wishes 2002- 181428 2. 3. 4. 5.] Claiming domestic priority (Article 25 of the Patent Law): [format please follow: application day; application note number sequence notes] 1. 2.] claiming patent law Article 26 Microorganisms: Domestic microorganisms [Please follow the format: deposit institution; date; number sequence notes] Foreign microorganisms [Please follow the format: deposit country name; institution; date; number sequence notes] It is easy for those familiar with the technology Obtained without deposit.