JPH07215875A - Stable cefotiam hydrochloride preparation - Google Patents

Abstract

PURPOSE:To obtain a cefotiam hydrochloride preparation having stability and solubility at the same time and accordingly extremely advantageous in economic aspects. CONSTITUTION:This cefotiam hydrochloride preparation is a stable preparation which is composed of a layer of cefotiam hydrochloride produced by the iyophilization of an aqueous solution of cefotiam hydrochloride and a layer of a pH adjuster, e.g. sodium dihydrogenphosphate, potassium dihydrogenphosphate, sodium citrate or trometamol.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stable cefotiam hydrochloride preparation, and more particularly to a cefotiam hydrochloride preparation which is stable even after long-term storage and is easily soluble in water.

[0002]

PRIOR ART The following formula (I)

[Chemical 1] It has been known for a long time that cefotiam represented by the formula or a salt thereof has excellent antibacterial activity (West German Patent Publication 2).
No. 461478), which is marketed as an antibiotic.

However, this substance has poor storage stability,
Further, there is a drawback that the solubility is poor when used as an injection. Therefore, as a method for solving these drawbacks, it is known to use a hydrous crystal of a specific cefotiam hydrochloride (Japanese Patent Publication No. 60-3314) and a method of combining with a carbonate (Japanese Patent Publication No. 56-36174). There is.

[0004]

However, in order to prepare a cefotiam hydrochloride preparation which is sufficiently satisfactory as a commercial product, these two methods must be combined, and the development of a simpler method has been desired. .

[0005]

In view of the above situation, the present inventor has conducted diligent research to obtain a cefotiam hydrochloride formulation capable of achieving both storage stability and solubility in water, and as a result, freeze-dried hydrochloric acid was obtained. On top of the layer of Cefotiam, pH
The present invention has been completed by finding that the purpose can be achieved by providing a modifier layer.

That is, the present invention provides a stable cefotiam hydrochloride preparation comprising a cefotiam hydrochloride layer obtained by freeze-drying an aqueous cefotiam hydrochloride solution and a pH adjusting agent layer.

As shown in FIG. 1, the cefotiam hydrochloride preparation of the present invention comprises a pH adjusting agent layer 2 on a cefotiam hydrochloride layer 1 obtained by freeze-drying an aqueous cefotiam hydrochloride solution in a container 3 such as an ampoule or a vial. Are laminated.

Of these, the cefotiam hydrochloride layer 1 is prepared by dissolving cefotiam hydrochloride in purified water or the like together with an inorganic salt and a saccharide, if necessary, and freeze-drying. Freeze-drying may be carried out by filling container 3 with an aqueous solution of cefotiam hydrochloride, and freeze-drying this in a conventional manner. The cefotiam hydrochloride concentration of the aqueous solution used is 1 g titer / 1 ml.
A titer of about 1 g / 20 ml is preferable.

Examples of inorganic salts that can be freeze-dried with cefotiam hydrochloride include sodium chloride, calcium chloride and magnesium chloride, and examples of sugars include polyhydric alcohols represented by mannitol, glucose and fructose. , Maltose and the like, respectively. These inorganic salts and sugars are 0.1% less than cefotiam hydrochloride.
It is preferable to use an amount of about 10 mM / 1 g titer.

The pH adjusting agent layer 2 is formed by forming the cefotiam hydrochloride layer 1 by freeze-drying and then filling the layer with a powdery pH adjusting agent to form a layer.

Examples of preferable pH adjusting agents include sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium citrate, trometamol and the like. An anhydrous substance is usually used as the pH adjusting agent, but a salt having water of crystallization may be used, and the addition amount thereof is preferably about 10 mg to 1000 mg per vial.

If necessary, other suitable additive components such as trisodium phosphate, sodium hydrogen sulfite, sodium pyrosulfite, sodium carbonate and the like can be added. Further, if necessary, it is possible to add the inorganic salt or saccharide added to the cefotiam hydrochloride layer to the pH adjusting agent layer.

The cefotiam hydrochloride preparation of the present invention obtained as described above is used as a liquid by injecting distilled water for injection at the time of use.

[0014]

The present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

Example 1 (1) Cefotiam hydrochloride bulk powder in an amount to give a titer of 0.5 g was placed in a 30 ml vial, and this was used for injection 2.
After dissolving with 5 ml, freeze-drying device (72FS100
Type; manufactured by Hull Co., Ltd.) and freeze-dried under the following conditions to form a freeze-dried powder layer of cefotiam hydrochloride in a vial. (Freeze-drying condition) Freezing temperature -40 ° C Primary drying temperature 5 ° C Secondary drying temperature 30 ° C Airness 50μHg or less

(2) In the vial obtained in (1) above, 200 mg of trometamol, 55 mg of anhydrous sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate 140
A mixed powder of mg was evenly dispersed to form a pH adjusting agent layer. Finally, the vial was sealed to obtain a cefotiam hydrochloride formulation (formulation 1 of the present invention).

Example 2 The preparation 2 of the present invention was prepared in the same manner as in Example 1 except that 300 mg of disodium hydrogen phosphate was used instead of the mixed powder of trometamol, anhydrous sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate. Obtained.

Test Example 1 The solubility of the preparations of the present invention obtained in Examples 1 and 2 was examined by the following method, and bulk powder and a commercially available product (for intravenous injection of pansporine; 0.5 g titer / cefotiam hydrochloride) were tested. A hydrous crystal of a salt was used, and it was compared with a formulation in which this was combined with a carbonate). The results are shown in Table 1.

(Solubility Measurement Method) Each of the formulation vials of the present invention,
After setting the commercially available product and Cefotiam hydrochloride bulk powder filled in a vial on a shaker (KM Shaker V-DX type; manufactured by Iwaki Sangyo), 20 ml of purified water is gently added. Then, shaking is performed at 245 times / minute and an amplitude of 40 mm for 15 seconds, and then, standing is performed for 30 seconds. This shaking-standing cycle is repeated, and the solubility at the time of shaking is evaluated by the total time when no particles are observed in the vial. The shaking number is a level at which water in the vial starts to move obviously by shaking.

(Result)

As is clear from these results, the bulk powder of cefotiam hydrochloride is difficult to dissolve, but the formulation of the present invention was able to obtain the same solubility as the commercially available product.

Test Example 2 Cefotiam hydrochloride preparations prepared in Examples 1 and 2
It was stored in a constant temperature bath at 0 ° C. for 2 weeks, and the residual amount of cefotiam was measured. The results are shown in Table 2.

[0023]

As is clear from these results, all the formulations of the present invention had sufficient stability.

[0025]

EFFECTS OF THE INVENTION The cefotianum hydrochloride preparation of the present invention has both stability and solubility, and is therefore extremely economically advantageous.

[Brief description of drawings]

FIG. 1 is a diagram (cross-sectional view) schematically showing the constitution of the preparation of the present invention.

[Explanation of symbols]

 1 ... Cefotiam hydrochloride layer 2 ... pH adjusting agent layer 3 ... Container 4 ... Cap and above

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[Procedure amendment]

[Submission date] February 22, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction content]

Example 2 Preparation 2 of the present invention was carried out in the same manner as in Example 1 except that 300 mg of anhydrous disodium hydrogen phosphate was used instead of the mixed powder of trometamol, anhydrous sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate. Got

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Claims (1)

[Claims] 1. A stable cefotiam hydrochloride preparation comprising a cefotiam hydrochloride layer obtained by freeze-drying an aqueous cefotiam hydrochloride solution and a pH adjusting agent layer.