JPH01250322A - Antibiotic composition - Google Patents

Abstract

PURPOSE:To obtain an antibiotic composition containing hydrochloride of SCE-2787 and basic substance, free from deposition of an insoluble product after dissolving and having suppressed local action and emolysis. CONSTITUTION:A hydrochloride of 7beta-[(Z)-2-(5-amino-1,2,4-thiaziazol-3-yl)-2- methoxyiminoacetamide]-3-(1-imidazo[1, 2-b]-pyridazinium) methyl-3-cephem-4- carboxylate (SCF-2787) expressed by the formula and exhibiting strong antibacterial action to grampositive bacterium as well as gram-negative bacterium containing bacillus pyocyaneus and further exhibiting relatively strong effectiveness also to mesitine-cephem resistant Staphylococcus infectious disease and being an antibiotic which is extremely useful as an antibacterial agent and basic substance (preferably alkali metal carbonate) which is pharmaceutically acceptable are contained at a ratio of normally 1:0.5-5.0 equivalent, especially 1:1.4-2.0 equivalent.

Description

[Detailed description of the invention] Jujube direct Δ outside the weighing plate” The present invention relates to antibiotic compositions.

Prior art 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl]-2-methoxyiminoacetamide]-3-(1-imidazo[1,2- b]-pyridazinium)methyl-3-cephem-4-carboxylate (
(hereinafter abbreviated as 5CE-2787) is JP-A-62-14
Methicin, a compound represented by formula (1) specifically disclosed in 9682, has strong antibacterial activity not only against Durham-positive bacteria but also against Gram-negative bacteria including Pseudomonas aeruginosa. −Cephem-resistant Staphylococcus (
It is an extremely useful antibiotic as an antibacterial agent as it shows relatively strong efficacy against MR9A) infections.

Problems to be Solved by the Invention 5CE-2787 itself is a compound that exhibits excellent antibacterial activity as described above, but it has the drawback of being difficult to dissolve in water. Furthermore, 5CE-2787 is its hydrochloride (hereinafter, 5
Although the solubility in water can be improved by using 5CE-2787 (abbreviated as HCC),
When 2787 (HCf2) is dissolved in a dissolving solution such as distilled water during injection administration, the dissolution rate is slower than that of ordinary powder injections (also, even if it is dissolved to a certain degree, insoluble matter is generated over time as shown in the table). There is a problem in that it precipitates.

Table: Change in solubility after dissolution (25°C) (Method for determining solubility) 1: Clear+: Mixed (fine insoluble matter suspended) ++; Insoluble matter suspended +++: Insoluble matter sedimented Therefore, administer 5CE-2787 (HCg) In order to achieve this, it is necessary to administer immediately after dissolution, or to use an extremely diluted solution (less than Img/d); however, in the former case, crystals may form between the time of preparation in the dispensing room and the time of administration. may precipitate. In addition, the latter method is extremely undesirable in terms of injection formulations since it requires ensuring an effective concentration and a large volume of injection solution, and improvements are desired.

Due to its low pH, Sarani 5CE-2787 (HC&) is expected to cause local effects such as necrosis, whitening, browning, and bleeding of muscle cells at the injection site and hemolysis when injected intramuscularly.
Improvements are also desired in this regard.

Therefore, an object of the present invention is to provide an injection preparation in which the solubility of 5CE-2787 and/or 5CE-2787 (HCl2) is improved and the above-mentioned local effects and hemolytic effects are suppressed.

Means for Solving the Problems The present inventors have made extensive studies to solve the above-mentioned problems, and have unexpectedly found that 5CE-2787 (HCQ) has a pharmacologically acceptable basic substance ( By incorporating 5CE (hereinafter referred to simply as non-toxic basic substance)
-2787 () (C12) without impairing its storage stability (insoluble matter precipitation and stability of active ingredients, etc.), (1) SCE-2
After dissolution of 787 (HCl2), its Hoff is neutralized by a non-toxic basic substance to form 5CE-2787, but there is no precipitation of insoluble matter after dissolution, and (2) the above-mentioned local effects and hemolytic effects It was discovered that the problems such as the disappearance of the problem were solved at the same time, and after further study, the present invention was completed.

That is, the present invention provides 7β-[2-(5-amino-1,2
,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamide]-3-[(imidazo[1,2-b
]-pyridazinium)methyl]-3-cephemu 4-carboxylate hydrochloride and a pharmacologically acceptable basic substance.

The S CE-2787 (HCl2) crystals used in the present invention are generally prepared from 5CE-2787 in the presence of water and an organic solvent.
It is produced by reacting with hydrochloric acid or hydrogen chloride, collecting the crystallized crystals, and optionally removing the crystals from an organic solvent to convert them into 5CE-2787 (1-Ice) crystals that are not organically solvated. be able to. In this case 5CE-
As 2787, crystalline form of 6 can also be used.

Alternatively, crystals of 5CE-2787 (HC&) are solid 5
It can also be produced by reacting CE-2787 with hydrogen chloride gas. This method has the advantage of not requiring any step of using an organophilic solvent.

In addition, for the first crystallization of S CE-2787 (HCg) of the present invention, 5CE-2787 crystals were dissolved in dilute hydrochloric acid, concentrated to about half the volume, dimethylformamide was added,
While rubbing the vessel walls at room temperature, acetone was gradually added to allow crystallization. By using the crystals thus obtained as seed crystals, hydrogen chloride or hydrochloric acid and 5C
E-2787 was reacted to form 5CE-27 under various conditions.
87 (HC&) became possible to crystallize.

5CE-2787, which is a raw material for the composition of the present invention, can be used, for example, in Example 1 of the above-mentioned JP-A-62-149682.
It is produced in an amorphous state according to the method described in 3.

Crystals of 5CE-2787 can be produced by dissolving an amorphous powder of 5CE-2787 in a small amount of water, or by purifying and condensing it by a conventional method. Also, 5CE-2
787 (It can also be produced by neutralizing an aqueous HC□ solution with an alkali such as sodium hydrogen carbonate.

To explain in more detail the ``biped manufacturing method'' of 5CE-2787 (1-ICQ) that does not use organic solvents, it is possible to use normally solid 5CE.
-2787 is brought into contact with a gas containing HCQ gas at a concentration of about 0.01% to about 3%, preferably about 0.05% to about 2%. As a gas for diluting such HCl2 gas, carbon dioxide, nitrogen, or the like is preferable. In this method, it is often convenient to use crystalline 5CE-2787 as the starting material.

S CE-2787 (MCI2) in the presence of organic solvents
The production of crystals is usually 0.1 parts by weight or more (the upper limit is not limited, but from an economic point of view it is preferably about 10 parts by weight) per 1 type assembly of 5CE-2787 (amorphous but crystalline). ) Desirably in the presence of 1 to 5 parts of water and an organic solvent of about 1 to 10 times the amount of the water used, 1 equivalent or more (again, the upper limit is not limited, but from an economical point of view up to about 5 equivalents) (generally preferred) hydrochloric acid.

Examples of organic solvents include ketones (e.g., acetone), ethers (e.g., tetrahydrofuran), lower alcohols (e.g., methanol, ethanol, etc.), esters (e.g.,
ethyl acetate, etc.), hydrocarbons (e.g., benzene), amides (e.g., N,N-dimethylformamide), nitriles (e.g., acetonitrile), halogenated hydrocarbons (e.g.,
methylene chloride) etc. are used.

HCQ may be used as an aqueous solution of hydrochloric acid or as a solution of the above-mentioned solvents, or as a solution of 5C in water and an organic solvent.
It may also be used by blowing hydrogen chloride into a solution or suspension of E-2787 (crystalline or pure). 5CE-278 in the presence of water and organic solvent as described above.
The reaction between 7 and HCC occurs immediately, but the time required to crystallize them depends on the water, organic solvent and MC used.
Although it depends on the amount of I2, etc., in order to increase the yield, it is preferable to spend about 5 minutes to about one day and night.

The crystals of 5CE-2787 (HCQ) of the present invention are more preferably obtained generally by dissolving or suspending 5CE-2787 crystals in water and adding hydrochloric acid, or directly dissolving 5CE-2787 in hydrochloric acid and adding an organic solvent. The crystals can be collected by filtering or the like. Furthermore, the batter solvate obtained here can be converted into a crystalline form of 5CE-2787 (HCQ) that is not organically solvated by subjecting it to a ``deorganic solvent.''

The organic solvate of 5CE-2787 (HCQ) is, for example, in the case of acetone solvate, 5CE-2787 (crystal)
1/3 to IO weight part preferably 1/3 to 1 weight part
5CE-2787 (I
-1 cc) It is more preferable to obtain the acetonate by extracting the acetonate. 5CE-2 thus obtained
787 (HCC) acetone hydrate usually contains 0.5 to 1 equivalent of acetone. In the case of ethanolate, 5CE-2787 ([-1cf2) ethanolate can be obtained by adding 2 to 5 times the amount of ethanol, preferably 2 to 3 times the amount of ethanol, of the water used for the hydrochloric acid solution of 5CE-2787 mentioned above. It is preferably obtained by crystallizing. The 5CE-2787 (MCI2) ethanolate obtained here usually contains 0.5 to 1.5 equivalents of ethanol.

Furthermore, S CE-278 efficiently obtained as described above
7(HCQ) acetone hydrate with ethanol, methanol,
Tetrahydrofuran, ethyl acetate, benzene, N, N-
The corresponding solvates can be prepared by stirring in the above-mentioned organic solvents such as dimethylformamide. Alternatively, the ethanolate can also be produced by bubbling nitrogen saturated with ethanol through the acetonate. Each of the obtained SCE-2787 (MCI2) solvates exhibits crystallinity by powder X-ray diffraction. Obtained 5CE-278
7(HCff) solvate has high purity and good stability.

On the other hand, among the solvates obtained in this way, it is desirable to remove such organic solvents when using them for medicine, but when using normal vacuum drying etc., 5CE-2787 (It is difficult to remove the solvent sufficiently without damaging HC(2) itself. In order to solve this problem, in the present invention, high temperature without making it
The solvent can be efficiently removed. 5CE-278
After removing the solvent, 7 (HCC) can also be dried by a conventional drying method such as vacuum drying or blow drying.

For example, 5CE-2787 (HCN) 7) hydrate, SC
5CE- such as E-2787 (MCI2) ethanolate
The 2787 solvate can be desolvated, for example by supercritical gas extraction using carbon dioxide, as follows. In the humidification method, humidified air or nitrogen having a relative humidity of 50 to 90%, preferably 60 to 80%, is passed through the sample to remove the solvent according to a conventional method known per se. Thus obtained S CE-2787 (MCI2) +;i powder
Linear diffraction shows crystallinity.

Supercritical gas extraction involves filling an extractor with a solid cephalosporin compound and passing supercritical carbon dioxide through it continuously or intermittently. This is done by extracting the solvent. The preferred extractor used in the present invention is a pressure vessel and usually has a temperature control mechanism. In terms of pressure resistance, it is necessary to withstand a critical pressure cuff of carbon dioxide of 5.3 kg/c11+' (absolute pressure) or higher, but it is usually 10
0 to 500 kg/cam''.The shape of the extractor is not particularly limited, but a vertical cylindrical tank having a gas inlet/outlet nozzle, a nozzle or a lid for filling and extracting the solid cephalosporin compound is preferable. A mechanism is required to hold the solid cephalosporin compound within the particle size of the solid cephalosporin compound.

Various types can be selected from the viewpoints of corrosion resistance, ease of loading and unloading, and economic efficiency of equipment. For example, a perforated plate is installed at the bottom of the tank, and a filter cloth or metal mesh (e.g., made of stainless steel) is stretched to hold it in place; a method of installing a porous sintered metal (e.g., stainless steel) or ceramic filter; a method of installing a filter made of porous sintered metal (e.g., stainless steel); The most suitable method can be selected depending on the purpose, such as filling a solid cephalosporin compound into a cylindrical container (for example, made of stainless steel) or a cylindrical container lined with a filter cloth and installing it in the extractor.

An example of a simple device used in the method of the present invention is shown in FIGS. 1 and 2.

FIG. 1 shows an example in which gaseous carbon dioxide is supplied from the top of a carbon dioxide cylinder, and FIG. 2 shows an example in which liquefied carbon dioxide is supplied directly from the bottom of the carbon dioxide cylinder.

In Figures 1 and 2, supercritical carbon dioxide is extracted using an extractor l.
The water flows from the top to the bottom, but the reverse is also possible. In this case, it is preferable to install a filter at the top of the container or near the outlet of the container in order to eliminate loss of the powdered cephalosporin compound and to prevent clogging of piping and valves in the exhaust system.

The supercritical carbon dioxide used in the method of the present invention is preferably carbon dioxide at a critical temperature of 31.1° C. and a critical pressure of 5.3 kg/am absolute pressure.

The supercritical carbon dioxide used in the method of the present invention may be used as long as the critical temperature of carbon dioxide is 31.1'C or higher, but from the viewpoint of temperature controllability and thermal stability of the cephalosporin compound, it is 35 to 50°C. degree is preferred.

Also, the pressure of supercritical carbon dioxide is the critical pressure cuff 5 of carbon dioxide.
．． 3 kg/cm" (absolute pressure) or more is fine, but from the viewpoint of pressure controllability and economical efficiency, it is 80 to 300 kg.
The flow rate of supercritical carbon dioxide is preferably about 0.5 to 50 kg/hour per 1 kg of solid cephalosporin compound, although there is no particular restriction on the flow rate of supercritical carbon dioxide.

It is also possible to use conditions similar to conventional humidification desolvation methods, such as using humidified supercritical carbon dioxide or adjusting the moisture content of a solid cephalosporin compound before desolvation. For example, about 0.1 to 5% (W/W%) of water vapor to supercritical carbon dioxide may be added to the solid cephalosporin compound, or 5 to 50% of the amount of the cephalosporin compound obtained after drying may be added to the solid cephalosporin compound. (W/Y%) of water may be added and the solvent may be removed using supercritical carbon dioxide.

If the cephalosporin compound contains multiple solvents,
These solvents can be desolvated simultaneously. The solid cephalosporin compound is preferably ground in advance into a powder form.

In the humidification method, humidified air or nitrogen with a relative humidity of 50 to 90%, preferably 60 to 80%, is added to 5CE-278.
7(HCQ) The organic solvate is aerated and the organic solvent can be removed according to a conventional method. 5CE-2787 thus obtained (
HCC) shows crystallinity by powder X-ray diffraction.

Examples of crystals of S CE-2787 (HCC) include the following three typical crystal forms.

That is, (A) the lattice spacing (d
) Rikigetsu 4.2.7.4, 4.9, 4.7, 4.1゜3.
Crystal form having a powder X-ray diffraction pattern showing characteristic peaks at 8, 3.7, 3.5, 3.4, 3.3 (Reference Example 17)
(crystal, etc.), (B) lattice spacing (d
) is 8.6, 6, 5.5.4, 4.2°3.6, 3.4
(C) A crystal form having a powder X-ray diffraction pattern having a characteristic peak in the powder X-ray diffraction pattern (such as the crystal of Reference Example 9), and (C) a lattice spacing (d) of 7.3, 7° and 0.6° as shown in FIG. 6,5.3,
Examples include crystal forms (such as the crystal of Reference Example I4) having a powder X-ray diffraction pattern in which characteristic peaks appear at 4.9.4.8.4.0, 3.6°3.4.

The pharmacologically acceptable (i.e., non-toxic) basic substances used in the present invention include, for example, alkali metal or alkaline earth metal carbonates such as sodium bicarbonate and sodium carbonate, such as disodium phosphate. , inorganic bases other than carbonates such as dipotassium phosphate, organic bases such as methylglucamine tris(hydroquine methyl)aminomethane, and L-arginine, but are limited to these examples. isn't it. In short, since it is used in the chemical field as a non-toxic basic substance, any water-soluble substance can be advantageously used in the present invention. Among the bases mentioned above, alkali metal carbonates represented by sodium carbonate and sodium bicarbonate are usually conveniently applied.

The mixing ratio of 5CE-2787 (HCQ) and the non-toxic basic substance is such that the ratio of HCl2 (hydrogen chloride) and the non-toxic basic substance constituting S CE-2787 (HCff) is usually about 1:0. 5-5.0 equivalents, more preferably about 1:1
．． About 2 to 3.0 equivalents, more preferably about 1:1.4 to
It is preferable to set the amount to 2.0 equivalent.

Therefore, monoacid bases such as sodium bicarbonate and methylglucamine are usually about 0.5 to 2.5 moles, preferably about 1.2 to 2.5 moles, relative to 5CE-2787() [Cl2].
About 0 mol, and diacid salts such as sodium carbonate are usually 0.
It is preferable to mix it in an amount of about 25 to 2.500 moles, preferably about 0.6 to 1.5 moles.

The antibiotic composition of the present invention is 5CE-2787 (HCl2
) and a non-toxic basic substance in the above-mentioned ratio by a method known per se. At this time, if necessary, known pharmaceutical additives such as local anesthetics such as lidocaine hydrochloride and mepivacaine hydrochloride may be added to the extent that the effects of the present invention are not impaired. 5CE-2787 (HC
12) and non-toxic basic substances are usually used in powder or crystal form, and the composition of the present invention is usually solid.

For example, when filling the 5CE-2787 (HCC) of the present invention and carbonates into a vial, after filling them,
Normally, if the inside of the vial is evacuated and the vial is sealed (hereinafter sometimes abbreviated as vacuum seal for convenience), oxidative decomposition can be prevented, and at the time of use, distilled water for injection, physiological saline, 1 aqueous solution of local anesthetic, etc. It is easy to inject the solution, and carbon dioxide gas is generated, which significantly accelerates the dissolution rate of the main drug. Therefore, it is particularly suitable because rapid dissolution in a stationary state is possible. Furthermore, in this case, since the space inside the vial is filled with the generated carbon dioxide gas, the obtained 5CE-2787 solution has the advantage that it is stable without being oxidized and decomposed, and can be stored even after dissolution. The degree of vacuum inside the vial when sealing is usually about θ~5
00 a+mHg, more preferably about 0 to 100 mmH
It is g. The amount of solution added is usually about 1 to 5cE-27871g! 0014(l Omg/PR1-1
g/-).

For example, when using inorganic bases and organic bases other than carbonates, a solution containing these bases may be used. , :5CE-278'? 5CE-2787CHCQ) solution may be prepared by adding (MCI2). In this case, the 5CE-2787(s]cQ) solution is usually filled into a container after being sterilized and filtered. Moreover, for example, these may be further subjected to freeze-drying. In the case of the freeze-dried preparation for injection thus obtained, it can be easily dissolved at the time of use by injecting an aqueous solution of distilled water for injection, physiological saline, and local anesthetic. The addition m of the dissolving solution is usually about 1-100 m for 5CE-27871 g, which is the same as in the case of blending with carbonates.

5CE-2787()IC12 obtained in this way
) solution can be used not only as a topical disinfectant, e.g. as a disinfectant for surgical instruments, hospital rooms, drinking water, etc., but also against Gram-positive bacteria and Gram-positive bacteria, e.g. for warm-blooded animals such as humans, mice, rats, and dogs. It is administered by intramuscular or intravenous injection as a treatment for infectious diseases caused by negative bacteria.

When used as an external disinfectant for surgical instruments, 5CE
It is sufficient to prepare an aqueous solution of approximately 100 μg/d in terms of -2787 and spray it on surgical instruments.
Approximately 5 to 50111 g/kg in terms of E-2787,
S CE-2787 (preferably divided into 3 to 4 times a day)
The MCI2) solution may be injected intramuscularly or intravenously. As an embodiment of the present invention, it can be supplied, for example, in a vial or ampoule as shown in FIG.

Effects of the Invention When the antibiotic composition of the present invention is used as an injection, local effects, bleeding, etc. are suppressed, and storage stability is excellent, and solubility is further improved, and in particular, changes in solubility over time are not observed. I can't.

EXAMPLES The present invention will be explained in more detail by showing examples and reference examples below, but the present invention should not be limited to these.

In the following reference examples, the stability data were obtained by measuring the residual rate by high performance liquid chromatography after storage for the stated period under the respective described conditions. Also, % means "w/w%" unless otherwise specified.

Reference Example 1 Production of 5CE-2787 (crystal) from 5CE-2787 (innocent) Example of JP-A-62-149682! 5CE-2787 lyophilized product obtained according to 3 (main island is in amorphous form)
100 g was dissolved in 400 g of distilled water and stirred at room temperature for 1.5 hours to cause crystallization. Filter the obtained crystals and add distilled water +00
After washing with d and drying under reduced pressure, 5CE-2787 (crystal) 7
7.6g was obtained.

Elemental analysis value CIeHl? N IIs to s・3.
3HtO calculation value: C39,89: )I 4,14;
N 21,92:S 11.15 Actual value: C, 39J1. H3, 88, N 21.9
2゜Sli, 45 Reference Example 2 Production of 5CE-2787 (crystals) from a hydrochloric acid solution of SCE-2787 56.6 g of 5CE-2787 (crystals) obtained in Reference Example 1 was suspended in 300% of distilled water, and IN- Add 100 cc of hydrochloric acid to dissolve. This solution was purified using anhydrous sodium carbonate.
Adjusted to H about 4. The mixture was kept at room temperature for 3 hours, shaking occasionally, and then taken out. The obtained crystals were washed with 150% distilled water and dried under reduced pressure to obtain 42.4 g of 5CE-2787 (crystals).

Reference Example 3 Production of SCB-2787 (HC5X purity) 1 g of 5CE-2787 (crystal) 515II obtained in Reference Example 1 was suspended in 20 d of distilled water, IN-hydrochloric acid + d was added, and lyophilized to produce 5CE-2787 ( HCQ) (free quality) was obtained. The main island contains 3.5% water.

Elemental analysis value C+, FIraNecQosSt・2.5
H,0 calculated value: C38,22, H3,88, N 21.
11: CQ 5.94 Actual value: C38.04; H4.05: N 21
．． 26; C125,87 The stability of the ice crystals at 40° C. for one week was 94% survival rate.

Reference Example 4 Crystals of 5CE-2787 (HCQ) acetone hydrate from SCE-2787 11.3 g of 5CE-2787 (crystals) obtained in Reference Example I was dissolved in IN-hydrochloric acid 20-, and 77 g of acetone was added with stirring. After gradually adding the mixture, the mixture was stirred at room temperature for 7 hours to cause crystallization. The obtained crystals were collected by filtration and mixed with 20 d of acetone:water (6:1).
After washing with 40d of acetone and drying with air, 5C
7.6 g of E-2787()HCQ)acetonate was obtained. The ice crystals contained 2.6% water and 8.0% acetone (0.85 mol). The stability of the ice crystals at 40°C and 60°C for 8 days was 98% and 97%, respectively.

Reference Example 5 Crystal of 5CE-2787 (HCQ) acetonate from SCE-2787 138° 4 g of 5CE-2787 (crystal) obtained in Reference Example 1
Dissolved in 3N-hydrochloric acid 240ml, acetone 720+n1
was gradually added with stirring, and then seed crystals (crystals obtained in Reference Example 16 below) were added and stirred at room temperature for 2 hours to cause crystallization. Further, 3601 u of acetone was added dropwise over 1 hour while stirring, and the product was stirred for 4 hours after dropping and discharged.

The obtained crystals were collected by filtration and mixed with acetone:water (6:l) 1
After washing for 95 days with acetone and 480 hours of acetone, drying with dry air was performed to obtain S CE-2787 (1-HCl2
) 126.6 g of acetone hydrate was obtained. Ice crystals have a water content of 5.3
%, acetone 7.3% (0.8 mol).

Reference Example 6 Crystals of ethanolate of 5CE-2787CHC (1) from SCE-2787 11.2 g of 5CE-2787 (crystals) obtained in Reference Example 1 was dissolved in 3 Ld of 2N hydrochloric acid, and 60 volumes of ethanol was gradually added with stirring. After the addition, the mixture was stirred at room temperature for 30 hours and taken out. The obtained crystals were collected by filtration and washed with 50 d of a cooled mixture of ethanol and water (4:l).

Furthermore, after washing with 50 ethanol and drying with dry air, 5CE-2787 (HC (triethanolate 5.8
I got g. Ice crystals contain 4.8% water and 8.6% ethanol (
1.2 mol).

Reference Example 7 5CE from SCE-2787 (HCl2) acetone hydrate
Crystals of -2787(HCQ) ethanolate SCE-2787(HCl2) acetoneate obtained in Reference Example 5 3.
0 g was suspended in 30% of ethanol and stirred for 4.5 hours.

The obtained crystals were collected by filtration, washed with 35 ml of ethanol, dried with dry air, and then dried under reduced pressure to form 5CE-278.
28 g of 7(HCl2) ethanolate was obtained. The ice crystals contained 3.0% water and 7.5% ethanol (1.0 mol). The presence of acetone was not observed in the ice crystals based on NMrl. The stability of the ice crystals at 40°C and 60°C for 8 days was 98% and 98%, respectively.

Reference Example 8 5CE from SCE-2787 (HCl2) acetone hydrate
Crystals of -2787(HCN) meta/-ol hydrate 1 g of 5cE-2787(+-1c07 setone hydrate obtained in Reference Example 5) was suspended in methanol 10% and stirred at room temperature for 6 hours. After washing with 5 J of methanol, 890 mg of 5CE-2787 (IICQ) methanolate was obtained by blow drying with dry air.Ice crystals had a water content of 31%, and NMR
Approximately 1 mol of methanol was contained, and no acetone was observed.

Reference Example 9 SCE-2787 (1-1 (5 from 11-acetonate)
Crystals of CE-2787(1-1cf2) N,N-dimethylformamide 5CE-2787(I(C12) acetonate tg obtained in Reference Example 5) was suspended in 10d of N,N-dimethylformamide and stirred at room temperature. The resulting crystals were stirred for 6 hours.
After washing with dimethylpolamide 5, dry with dry air to obtain 5CE-2787(HCl2)N,N.
-; 625 mg of methylformamide hydrate was obtained. The ice crystals had a water content of 2.3%, NMR analysis showed that they contained approximately 1 mole of N,N-dimethylformamide, and no acetone was observed. The powder X-ray diffraction pattern of the main island is shown in Figure 5.

Reference Example IO Desolvation of 9CE-2787 (1-ICQ) acetone hydrate by supercritical gas extraction 5CE-2787 (MCI2) acetone hydrate obtained in Reference Example 5 was placed on a filter plate with a diameter of 25 cm and a height of 50 nm at the bottom. The container is filled into a vertical cylindrical container with a temperature of 4.
At 0°C, while adjusting the pressure inside the container to 200 kg/Cm', carbon dioxide was flowed downward from the top of the container through the powder layer to remove acetone by extraction. I did it. (Using the equipment shown in Figure 1) The main island contained 3.7% water and gas chromatography revealed that residual acetone was 0.5%.

1 [1 (KBr) cm-': 1784 NMR (DM
SO-da): 3.48 (2B, dd, J=26.
1°1L911z), 3.87 (3B, s), 5.
17 (1B, d, J = 5.4Hz).

5.50 (2H, broads), 5.85 (LH
, dd, J=9.0, 5.4Hz).

8.04 (IH, dd, J=9.0.4.5Hz),
8.41 (lH, d, J=1.811z), 8.4
1 (III, d, J = 1.811z), 8.85
(111, d, J = 1.811z), 8.98 (I
II, d, J=9.0112), 9.11(ill
, d, J=4.5t+z) Reference Example 2 Desolvation of SCE-2787 (HC/) ethanolate by supercritical gas extraction was obtained in Example 6, and ? ,=4 g of SCE-2787 (HCe) ethanolate was removed in the same manner as in Reference Example 10 to obtain 3.5 g of 5cE-2787 (HcQ).

The main island contained 2.7% water, and gas chromatography revealed that residual ethanol was less than 0.1%.

Motojima gave a NMFt spectrum similar to Reference Example IO. The stability of the main island for 3 weeks at 40°C and 60°C was 98% and 94%, respectively, in terms of survival rate.

Reference Example 12 5CE-2787 obtained in Reference Example 5 was placed on a humidified deorganized solvent plus filter of SCE-2787 (MCI2) acetonate.
Take 5.0 g of (HCQ) acetonate, pass through an aqueous layer at 10°C, send humidified air through a filter (flow rate 11112/min) to remove the solvent, and then dry under reduced pressure to obtain S CE
-2787 (MCI2) 4.85 g was obtained. The main island contained 8.2% water, and NMR revealed that residual acetone was less than 0.2%. Motojima gave an NMR spectrum similar to Reference Example IO.

Elemental analysis value C1゜H+5NeC120sSt・2.5
HtO calculation: C3g, 22; H3,8g, N
21.11: CQ 5.94 Actual value: C38,17, H3,56, N 21.02°Ca2.96 Reference example 13 Reference example 7 on a humidified desolvation glass filter of SCE-2787 (MCI2) ethanolate 5CE-2787 obtained from
(FICg) 4.0 g of ethanolate was passed through a saturated aqueous solution of sodium acetate, humidified air was sent through a filter to remove the solvent, and 5CE-27s7(+(cQ)3.
Obtained 0g. On the main island, residual ethanol was found to be less than 0.1% by gas chromatography. Obtained S CE-
2787 (I (CI2)) was dried under reduced pressure and used in the following examples, and its stability in various water-containing conditions was measured.The survival rate after one week and five weeks at 40°C and 60°C is shown in the table below.

Reference example 14 5CE-278 using gas diluted with nitrogen HCff
7 crystals (conversion to DSCE-2787 (HCff) crystals 5CE-2787 crystals 2 produced according to Reference Example 1,
5 g (moisture 2.4%) was filled into a vertical cylindrical glass filter with a diameter of 25III@, and 1% HCQ gas (diluted with nitrogen) at a flow rate of ff 1200 d/min and 1 g of the prototype 001R1
0,1 prepared by mixing nitrogen gas /min.
% HCl2 gas was passed through a calcium chloride U-tube while drying and flowed downward from the top of the container through the powder layer for 25 hours to convert SCE-2787() (C) into crystals. By pouring, SCE~2787 (HCf crystals) as shown in the powder X-ray diagram in FIG. 6 were obtained.

Reference example 15 5CE using gas diluted with I-ICU with carbon dioxide
Conversion of -2787 crystals to 5CE-2787 (HCf2) crystals 25 g of 5CE-2787 crystals produced according to Reference Example 1
(moisture 9.1%) into a container similar to Reference Example I4,
0.1% 14CQ gas prepared by mixing 1% HCl2 gas (diluted with nitrogen) with a flow rate of 1800 components/min and carbon dioxide gas at a flow rate of 720 oa/min was passed through a calcium chloride U-tube and dried from the top of the container. 5CE-2787 (HC
f2) Conversion to crystal was performed. Carbon dioxide gas was passed through this for 12 hours to obtain 5CE-2787 (HCQ) crystals. The main island contains 3.6% water, and the content was measured by high-performance liquid chromatography and Cρ by silver nitrate titration.
As a result of m content measurement, it contained 1.0 mol of HCρ.

Reference Example 16 Reference - 5CE-2787 (crystal) produced according to Example 1
563 mg was dissolved in 1N-HCf2+d and concentrated to about half the volume under reduced pressure. After adding DMF ld to the residue and dissolving it, stimulation with spatyl was continued while adding acetone 5 years old little by little, and crystallization occurred slowly at room temperature. The main island was confirmed to be crystalline by observation using a polarizing microscope.

Separately add 563 mg of 5CE-2787 (crystal) to lN-1-
When the mixture was dissolved in ICQl- and slowly added with acetone while stirring, the crystals obtained above were added as seed crystals at room temperature, and crystallization gradually occurred. The obtained crystals were collected by filtration under reduced pressure, washed with acetone, and dried under reduced pressure to obtain SCE-2787 (HCQ)2 as (NMR) crystals containing acetone.
80 mg was obtained. The main island has a water content of 2.6% and acetone 8.
Contains 0%.

Reference Example 17 5CE=2787(■-+
cC) Ethanolate crystals 3.0 g (9.9% ethanol, 0.83% water) were filled into a vertical cylindrical glass filter with a diameter of 25n+n+, and humidified nitrogen gas was passed through a water layer at 18°C. After aeration for 3 hours and desolvation, 5CE-2787 (
1-1c &) 3.0 g of crystals were obtained. The main island contained 13.7% water, and gas chromatography revealed that residual ethanol was less than 0.01%.

Example 1 5CE-27 obtained in Reference Example 6 in a vial with a content of 35 precepts
After filling the vial with 1.07 g of 87 (HCf2) crystals and 152.2 mg of anhydrous sodium carbonate, the inside of the vial was adjusted to 50 mmHg and the vial was sealed. In addition, when 3 d of distilled water for injection was added to this and dissolved, it was extremely easy to dissolve. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 2 Contents! :; After filling 0.54 g of 5cE-2787 (HcQ) crystals obtained in Reference Example 7 and 99.1 mg of anhydrous sodium carbonate into a vial with 117 h=1, the inside of the vial was heated to 50+.
It was adjusted to nmHg and sealed. To this, pharmacopoeia saline 3
It was extremely easy to dissolve by stirring. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 3 5CE-27 obtained in Reference Example 7 was placed in a vial with a content of 35 cm.
After filling 87 (H
The container was adjusted and sealed. When 20 volumes of distilled water for injection was added to this and dissolved, it was extremely easy to dissolve. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 4 5CE-2 obtained in Reference Example 7 in a vial with contents ff19d
After filling 0.268 g of 787 (HCQ) crystals and 60.3 mg of anhydrous magnesium carbonate, the inside of the vial was filled with 20 ffllll.
The pressure was adjusted to 1Hg and the cap was sealed. Distilled water for injection 3
- was added and dissolved, and the dissolution was extremely easy. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 5 56.0 g of methylglucamine was dissolved in 200-g distilled water for injection, and the SCE-2 obtained in Reference Example 1O was added to this solution.
Add 107.1 g of 787 (HCQ) crystals and dissolve with stirring.
The total volume was filled with 300ml of distilled water for injection.

After sterilization filtration, the contents! 1.5Ml in 1117d vial
Filled. The filled vial was lyophilized and made into an injection.

When 3 d of distilled water for injection was added to this and dissolved, it was extremely easy to dissolve. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 6 Disodium phosphate 12H*0 74.4g to 150
107.1 g of SCE-2787 (HC(2) crystals obtained in Reference Example 10) was dissolved in distilled water for injection.
Add, stir to dissolve, and add 200 dl of distilled water for injection.
And so. After sterilization and filtration, a vial with a content of ff19d was filled with 0.
5- was filled. The filled vial was lyophilized and made into an injection. When distilled water for injection 3- was added to this and dissolved, it was extremely easy to dissolve. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 7 In the method of Example 5, 34 g of tris(hydroxymethyl)aminomethane was used instead of 56.0 g of methylglucamine.
．． An antibiotic composition was obtained by using 7 g and performing the same treatment. When this composition was dissolved by adding 3 g of distilled water for injection, it was extremely easy to dissolve.

Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Implementation ρ18 5CE obtained in Reference Example 10 in a vial with contents ff117d
- After filling 1.12g of 2787 (HCl2) crystals and 164.5mg of anhydrous sodium carbonate, the inside of the vial was adjusted to 50mmH.
The mixture was adjusted to H and sealed. In addition, when 3 parts of distilled water for injection was added to this and dissolved, it was extremely easy to dissolve. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 9 5CE-2 obtained in Reference Example 1O was placed in a vial with a content of 17 d.
After filling the vial with 1.17 g of 787 (HCl2) crystals and 164.51 g of anhydrous sodium carbonate, the inside of the vial was adjusted to 50 mmHg and the vial was sealed. In addition, when 0.5% mepivacaine hydrochloride aqueous solution 3- was added and dissolved, dissolution was extremely easy. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 1O SCE obtained in Reference Example IO in a vial with a content of 130-
After filling 1.17 g of -2787 (1-ICQ) crystals and 164.5 g of anhydrous sodium carbonate, the inside of the vial was adjusted to 10 mmH.
g and sealed. In addition, when 1001 jl of physiological saline was added to this and dissolved, it was extremely easy to dissolve. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

Example 11 5CE-27 obtained in Reference Example 1O in an ampoule with a content of 2 volumes
After filling 335 μg of 87(I-[Cl2) crystals, 49.4 μg of anhydrous sodium carbonate, and 9 mg of sodium chloride, the container was melt-sealed. In addition, when 1 d of distilled water for injection was added to this and dissolved, it was extremely easy to dissolve. Further, even after 24 hours had passed after dissolution, no change in the solution state such as precipitation of insoluble matter was observed.

[Brief explanation of the drawing]

1 and 2 show the simplest apparatus used for desolvation by supercritical gas extraction according to the present invention. l...Extractor 5...Heater 2...Carbon dioxide cylinder 6...Pressure control valve 3...Condenser 4...High pressure metering pump Figure 1 Supplied from carbon dioxide cylinder 2 Carbon dioxide is liquefied in a condenser 3, and the high-pressure metering pump 4 pumps the liquid under pressure. The carbon dioxide is further heated to a predetermined temperature in a heater 5 to become supercritical carbon dioxide, and then enters the extractor 1, which is prefilled with a solid cephalosporin compound. The supercritical carbon dioxide contacts the solid cephalosporin compound to extract residual solvent and is then disposed of through the pressure regulating valve 6. Liquefied carbon dioxide is directly supplied from a carbon dioxide cylinder 2 in FIG. 2, and after pressurized liquid is sent by a high-pressure metering pump 4, it is converted into supercritical carbon dioxide by a heater 5. The following is the same as in Figure 1. FIG. 3 shows a diagram in which the antibiotic composition of the present invention is filled and the cap is evacuated. In FIG. 3, 1 represents an aluminum cap, 2 represents a rubber stopper, 3 represents the composition of the present invention, and 4 represents a vial. Figure 4 shows the powder X-ray diffraction diagram of the target product obtained in Reference Example 17 (
CuXα, 50KV, IOOmA). Figure 5 shows the powder X-ray diffraction diagram (C) of the target product obtained in Reference Example 9.
uXα, 40KV, 7 OmA). Figure 6 shows the powder X-ray diffraction diagram of the target product obtained in Reference Example 14 (
CuXα, 50KV, 100mA). Agent Patent Attorney Iwa 1) Hiroshi Figure 3

Claims (1)

[Claims] 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(1-imidazo[1,2-b]- pyridazinium) methyl-3-cephem-4-carboxylate.
An antibiotic composition comprising a hydrochloride and a pharmacologically acceptable basic substance.