Cephalosporin injection

A cephalosporin having the formula ##STR1## is stabilized in an injection solution with lactose and/or sodium chloride.

The present invention relates to a cephalosporin injection. Thus the 
present invention is employed in the field of medicines. 
A cephalosporin of the following general formula: 
##STR2## 
i.e. 
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3- 
(4-carbamoyl-1-quinuclidinio)-methyl-3-cephem-4-carboxylate and nontoxic 
salts thereof are denoted here as cephalosporin and have a strong 
antibacterial activity against Gram-negative bacilli of glucose 
non-fermentation type, such as Pseudomonas aeruginosa and Acinetobacter. 
Therefore, it would be expected to use them in injections against these 
bacilli. Since, however, these compounds are chemically unstable, 
coloration and reduction in the titer of them are observed in not only 
aqueous solutions but also dry powders. These phenomena are observed to 
proceed, for example, even in a powdery cephalosporin, which is to be 
dissolved in situ to form an injection, as time elapses. No satisfactory 
means of solving this problem has been developed yet. 
Under these circumstances, the inventors have sought a composition of an 
injection of the cephalosporin of the present invention in powdery form 
which is to be dissolved in situ and which can be protected from the 
coloration or reduction in the titer during storage. As a result, the 
inventors have found that the problem can be solved by incorporating one 
or both of lactose and sodium chloride in the above injection. The present 
invention has been completed on the basis of this finding. 
Now, the detailed description will be made on the present invention. 
The cephalosporin according to the present invention is 
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3- 
(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate or its nontoxic 
salt and is used as an injection. For example, 500 to 1,000 mg of the 
cephalosporin is administered by instillation. The cephalosporins have a 
wide anti-microbial spectrum ranging from Gram-positive microorganisms to 
Gram-negative ones. They exhibit a high antimicrobial activity 
particularly against Gram-negative bacilli of glucose non-fermentation 
type, such as Pseudomonas aeruginosa and Acinetobacter. Further, they are 
highly safe and effective on .beta.-lactamase-producing bacteria 
(Enterobacters and Citrobacters) which are resistant to cephem of the 
third generation. 
The invention provides an injection composition which comprises the above 
defined cephalosporin or a non-toxic salt thereof and lactose and/or 
sodium chloride. 
Further the invention provides an injection solution which comprises the 
above defined composition and an injection carrier. 
It is advantageous from the practical point of view that the injection 
solution comprises lactose and/or sodium chloride in such a total amount 
as to make a physiological solution. For instance it contains about 0.9 
wt.% of sodium chloride, about 5 wt.% of lactose or about 0.45 wt.% of 
sodium chloride and about 1.5 wt.% of lactose in combination. 
The cephalosporin according to the invention is a cephem derivative and is 
disclosed in U.S. patent application Serial No. 818 824 filed Jan. 14, 
1986 and the corresponding EPC patent application No. 86 100 357.2 filed 
Jan. 13, 1986, now published with EP-A 188 255. 
It is, for example, produced by dissolving 2 g of 
7.beta.-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylic 
acid hydrochloride in 40 ml of a mixture of acetonitrile and water mixed 
at 1:1, adding 2.08 ml of triethylamine to the solution, cooling it with 
ice, adding thereto 2.55 g of 
2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxyiminoacetylchl stirring the 
mixture for 50 minutes, adding the reaction mixture to 200 ml of ethanol, 
separating the deposited solid with filtration, washing the solid with 
ethanol and isopropylether to obtain 450 mg of the intended product which 
can be identified with the infrared absorption and the NMR analysis. 
Lactose and sodium chloride usable in the present invention are available 
on the market in, for example, the form of injection. They can be used 
either singly or in combination. The preferred amounts of them per part by 
weight of the cephalosporin of the present invention are as follows: When 
lactose is used singly, the amount thereof is at least 1 part by weight 
and when sodium chloride is used singly, the amount thereof is at least 
0.1 parts by weight. When a combination of them is used, the preferred 
amounts of them are as follows: in case the amount of lactose is less than 
0.25 parts by weight, the amount of sodium chloride is at least 0.1 parts 
by weight and in case the amount of lactose is at least 0.25 parts by 
weight, that of sodium chloride is at least 0.05 parts by weight. However, 
the amounts of them are not particularly limited to these ranges in the 
present invention. They are incorporated in the injection by dissolving 
them in water together with the cephalosporin of the present invention. 
The powdery injection to be dissolved in situ is provided mainly as a 
freeze-dried powder. For example, the cephalosporin of the present 
invention and lactose are dissolved in water, the solution is filtered 
under sterile conditions, a given amount of the solution is poured in a 
vial or ampoule and freeze-dried and the vial or ampoule is stopped or 
sealed by fusion. In another process, the solution is filtered under 
sterile conditions and freeze-dried into a powder, and a given amount of 
the powder is packed in a vial of ampoule. At the time of use, water for 
injection or the like is added to the powder to obtain a solution. 
The effect of the present invention is that coloration and reduction in the 
titer of the cephalosporin of the present invention with the lapse of time 
can be inhibited when the cephalosporin is used as a powdery injection 
dissolved in situ. This effect will be provided by an experimental example 
given below.

The following examples will further illustrate the present invention. 
EXAMPLE 1 
20 g of the cephalosporin of the present invention and 20 g of lactose were 
dissolved in distilled water to prepare 100 ml of a solution. The solution 
was filtered through a membrane filter under sterile conditions. 5-ml 
portions of the solution were poured into 100-ml vials and freeze-dried. 
The vials were stopperred. 
EXAMPLE 2 
20 g of the cephalosporin of the present invention and 4 g of sodium 
chloride were dissolved in distilled water to prepare 100 ml of a 
solution. The solution was filtered through a membrane filter under 
sterile conditions. The resulting solution was poured into a Petri dish to 
a depth of 10 mm and then freeze-dried under sterile conditions. 900-mg 
portions of the obtained powder were packed in 20-ml vials and the vials 
were stopperred. 
EXAMPLE 3 
20 g of the cephalosporin of the present invention, 1 g of lactose and 4 g 
of sodium chloride were dissolved in distilled water to prepare 100 ml of 
a solution. The solution was filtered through a membrane filter under 
sterile conditions. 10-ml portions of the resulting solution were poured 
into 10-ml vials and freeze-dried. The vials were stopperred. 
EXPERIMENTAL EXAMPLE 
Lactose and sodium chloride in amounts corresponding to the weight ratios 
shown in the column of the weight ratios of additives in Table 1 were 
added to 20 g of the cephalosporin of the present invention. Water was 
added thereto to prepare 100 ml of a solution. The solution was filtered 
through a membrane filter. 5-ml portions of the solution were poured into 
10-ml vials and then freeze-dried. The vials were stopperred to obtain 
samples. The samples were subjected to a storage test at 50.degree. C. for 
one month and a change in the appearance and the persistence were 
examined. The persistence was determined from the ratio of the peak 
heights of the sample and the standard to an internal reference according 
to high-performance liquid chromatography (CD.sub.254) wherein the 
stationary phase comprised YMS-ODS and the mobile phase comprised a 
mixture of water and methanol (92.8). 
Results 
The results are shown in Table 1, wherein symbols in the column of "change 
of appearance" have the following meaning: 
++: colored brown, 
+: colored yellow or orangy yellow, 
.+-.: colored pale yellow, and 
-: no color change. 
It is apparent from Table 1 that the use of lactose and sodium chloride 
either singly or in combination is effective in stabilizing the powdery 
injection of the cephalosporin of the present invention which is to be 
dissolved in situ. It may be understood that when lactose is used singly, 
its amount is preferably at least 1 part by weight and when sodium 
chloride is used singly, its amount is preferably at least 0.1 parts by 
weight, each per part by weight of the cephalosporin of the present 
invention. It will be understood also that in case they are used in 
combination, the amount of sodium chloride is preferably at least 0.1 
parts by weight when the lactose is less than 0.25 parts by weight and the 
amount of sodium chloride is preferably at least 0.05 parts by weight when 
the lactose is 0.25 parts by weight or more. 
TABLE 1 
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Weight ratio of 
additive 
Sodium Change of Persistence 
Lactose chloride appearance 
(%) 
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0 0 ++ 74.7 
0.05 0 ++ 75.7 
0.25 0 ++ 77.8 
0.5 0 + 81.2 
1.0 0 + 85.0 
0 0.05 ++ 84.5 
0 0.1 + 90.6 
0 0.2 + 93.2 
0.05 0.05 ++ 85.0 
0.05 0.1 + 90.0 
0.05 0.2 .+-. 92.7 
0.25 0.05 + 86.6 
0.25 0.1 + 90.7 
0.25 0.2 .+-. 93.2 
0.5 0.05 + 88.3 
0.5 0.1 - 90.8 
0.5 0.2 - 92.5 
1.0 0.05 - 87.7 
1.0 0.1 - 89.7 
1.0 0.2 - 91.9 
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