JP2635009C - - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stable elcatonin preparation comprising an alkali-treated glass ampoule filled with an aqueous solution composition containing elcatonin as an active ingredient. [0002] Elcatonin has a chemical name of 1-butyric acid-7- (L-2-aminobutyric acid) -26.
-L-aspartic acid-27-L-valine-29-L-alanine calcitonin (
Salmon) [1-butyric acid-7- (L-2-aminobutyric acid) -26-L-aspartic acid-27-L
-valine-29-L-alaninecalcitonin (salmon)], a drug used to improve pain in hypercalcemia, Paget's disease, or osteoporosis. [0003] Problems to be Solved by the Invention [0004] When this drug is used as an aqueous solution preparation, the activity of elcatonin may be reduced by vigorous shaking, and it is not always satisfactory as a preparation taking into account the stability to shaking. The stability was not good. Under the present circumstances, the mechanism of the activity reduction by shaking of an aqueous solution of peptides has not been sufficiently elucidated, and the present inventors have considered the above problems and have solved the heat stability as an injection which has been conventionally overcome. The aim is to maintain or further improve the current state of photostability and pain during inoculation into the human body, and there has been reported a solution to the decrease in activity due to shaking of aqueous solutions of peptides by adding a surfactant. However, there was a case where safety was a problem. In order to maintain the activity of elcatonin satisfactorily even without the addition of a surfactant, intensive studies were conducted. [0004] Therefore, the present inventors have surprisingly used an aqueous solution composition containing elcatonin as an active ingredient to fill the aqueous solution composition containing elcatonin as an active ingredient. In an injection container, which is a borosilicate glass container for ampoule pharmaceuticals, it has been found that a stable elcatonin preparation can be obtained by filling an aqueous solution composition containing elcatonin as an active ingredient in an alkali-treated borosilicate glass ampoule container. . Furthermore, it has been found that when the pH of the elcatonin aqueous solution composition is 5.0 to 6.5 and the ionic strength is μ = 0.01 to 0.5, a more stable and stable elcatonin preparation can be obtained. The present invention has been made based on such findings, that is, in the present invention, an ampoule container made of dealkalized borosilicate glass has a pH of 5.0 to 6.5 and an ionic strength of μ =
Lactate buffer having a pH of 0.01 to 0.5 or a pH of 5.5 and an ionic strength of μ =
The present invention relates to a stable elcatonin preparation filled with an aqueous composition containing elcatonin as an active ingredient, which contains a citrate buffer of 0.15. First, the main method for producing an aqueous solution composition containing elcatonin as an active ingredient of the present invention is, for example, a method of preparing an aqueous solution composition containing elcatonin as an active ingredient and having a pH of 5.0 to 6.0.
Lactate buffer having an ionic strength of μ = 0.01 to 0.5 or pH of 5.
5, and an effective amount of elcatonin is dissolved in a citrate buffer having an ionic strength of μ = 0.15 to prepare an elcatonin aqueous solution composition such as an elcatonin injection solution. In this case, both lactic acid and citric acid are used. It may be prepared at an appropriate molar concentration, preferably at a concentration of 0.05 to 20 mM, and particularly preferably, lactic acid or its sodium salt is prepared at a concentration of 0.05 to 20 mM. In addition, in preparing the aqueous solution of elcatonin, specifically, the pH is adjusted with a lactic acid or citrate buffer, and the ionic strength is calculated, and if necessary, non-toxic substances such as sodium chloride and potassium chloride are used. Addition of strong electrolyte inorganic salts, to obtain an aqueous medium with adjusted ionic strength, it is easy to further dissolve an effective amount of the active ingredient elcatonin, appropriately at the stage of preparation of the desired aqueous medium of elcatonin An effective amount may be dissolved, and the preparation order is not necessarily specified, and if necessary, other formulation components such as an isotonic agent, a soothing agent, a stabilizer, an absorption enhancer, and a preservative. Etc. can be added. In particular, the lactate buffer is a buffer containing lactic acid that can be added medically and has a buffering action capable of maintaining the pH of the final composition in the range of 5.0 to 6.5. Lactic acid or a salt thereof which can be medically added includes, for example, lactic acid or a salt thereof such as sodium lactate and potassium lactate as a preferred embodiment. The lactic acid or a salt thereof may be appropriately mixed with one or more of these, or a sodium salt or a potassium salt which is a water-soluble salt thereof,
The pH is adjusted to 5.0 to 6.5, and the pH may be finely adjusted as necessary with sodium hydroxide, hydrochloric acid, or the like. The amount of the pH buffer used may be the minimum amount that can buffer the pH of the aqueous solution of elcatonin to 5.0 to 6.5, and when the composition is used for injection, the amount used (in terms of molar concentration) ) Is 0.05 to 20 mmol, more preferably 0.1 to 5 mmol. The ionic strength is calculated according to the following formula, and the ionic strength is μ = 0.01 to
If necessary, adjustment may be made by adding sodium chloride, potassium chloride, or the like so as to be 0.5. Further, it is preferable that μ be adjusted to 0.04 to 0.3. . _{μ = 1/2 Σr i ·} z i 2 (r i: molar concentration of ion, z _i: its ionic valence) sodium chloride, the amount of the case of adding potassium chloride or the like, for example, 0.2
It is mentioned as a preferable aspect to use -1.2%. The effective content of the active ingredient elcatonin is, for example, usually 1 to 100 μg per milliliter of a solution, preferably 1 to 10 μg per milliliter of a solution in the case of an injection. In this case, the amount may be usually 1 to 100 μg per milliliter of the solution. The thus-obtained aqueous solution of elcatonin is injected into a glass container for parenteral administration of pharmaceuticals, for example, an ampoule, filled and filled in an aqueous solution for injection or the like, or a nasal solution of an aqueous solution by a conventional method. It can be a preparation such as a main agent. In particular, since the pH buffer solution of the elcatonin aqueous solution composition is dilute, the pH tends to fluctuate in a normal glass ampoule, for example, by contacting the inside of an ampoule formed of borosilicate glass with the surface of the glass container. PH changes due to external factors such as elution of an alkaline component from water, and the pH of the aqueous solution of elcatonin fluctuates. In such a case, a method of selectively washing and removing the alkali component on the surface of the glass ampoule container, for example, by adding a water-soluble sulfur such as sulfur dioxide gas or ammonium sulfate to the glass surface at a high temperature of about 250 to 800 ° C. By contacting the oxide, the alkali component on the surface is converted into fine sulfate crystals, and then subjected to a dealkalization-processed container for washing, that is, an ampoule container made of dealkalized borosilicate glass according to the present invention,
What is necessary is just to inject | pour and fill it by considering an appropriate effective amount of the said elcatonin aqueous solution composition by a conventional method. A preparation for parenteral administration comprising an ampoule container made of dealkalized borosilicate glass filled with the aqueous solution of elcatonin thus obtained improves the stability of elcatonin, and particularly has a molar concentration of 0. A formulation obtained by adjusting the pH to 5.0 to 6.5 and the ionic strength to μ = 0.01 to 0.5 using 0.5 to 20 mmol of lactic acid, and the molar concentration to 0.05 to 20 Formulations obtained by adjusting the pH to 5.5 and the ionic strength to μ = 0.15 using millimolar citric acid have particularly good shaking and heat stability of elcatonin and have been overcome in the past. In terms of photostability as an injection and reduction of pain upon inoculation into the human body, it was an excellent preparation which was not inferior to conventional products. Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples, comparative examples, or reference examples. REFERENCE EXAMPLE 1 Sodium acetate (trihydrate) (0.544 g) and sodium chloride (1.8 g) were dissolved in water to obtain a 200 ml solution.
(w / v) sodium chloride solution to 200 ml. 0.
0.7 ml of 002N hydrochloric acid was added and mixed, pH 5.5, ionic strength 0
. Adjusted to 15. Elcatonin (1.4 mg) was dissolved in 200 ml of the solution thus obtained to obtain an elcatonin aqueous solution composition. Since the pH buffer solution of the aqueous elcatonin aqueous solution composition is so thin that it tends to fluctuate in pH with a normal glass ampule, the ampoule subjected to dealkalization treatment (
A 0.5% ammonium sulfate aqueous solution was brought into contact with the inner wall surface of the ampoule, heated at about 600 ° C., then washed with distilled water for injection after ultrasonic cleaning, and dried at 250 ° C.), and 1 cc of the aqueous solution of elcatonin was used. Injections containing 7 μg of elcatonin were prepared by filling each 1 ml into a dealkalized glass ampoule for use.
Reference Example 1 preparation). The operations in the following Examples, Comparative Examples and Reference Examples were performed aseptically. Example 1 In the same manner as in Reference Example 1 above, lactic acid or its sodium salt was used as various monocarboxy compounds or salts thereof, and the same alkali-treated glass ampule as in Reference Example 1 was used. Elcatonin aqueous solution composition shown in No. 1 was obtained, and an injection containing 7 μg of elcatonin was produced in the same manner (Example 1 formulation). Example 2 In the same manner as in Reference Example 1 above, citric acid or its sodium salt was used as various polyvalent carboxy compounds or salts thereof, and the same alkali-treated glass ampule as in Reference Example 1 was used. An aqueous solution of elcatonin shown in Table 1 was obtained, and an injection containing 7 μg of elcatonin was prepared in the same manner (Example 2 preparation). REFERENCE EXAMPLE 2 The following comparison is given as a comparison with the reference example 1. 0.544 g of sodium acetate (trihydrate) and 1.8 g of sodium chloride were dissolved in water to obtain a 200 ml solution, which was designated as solution A. Separately 0.24 g of acetic acid
, 1.8 g of sodium chloride were dissolved in water to obtain a 200 ml solution, which was designated as solution B. 25 ml of solution B was added to 200 ml of solution A and mixed to adjust the pH to 5.5 and the ionic strength to 0.17. Elcatonin (1.4 mg) was dissolved in 200 ml of the solution thus obtained to obtain an elcatonin aqueous solution composition. Next, 1 ml of this elcatonin aqueous solution composition was filled into a glass ampoule for 1 cc (untreated with alkali-treatment) to prepare an injection containing 7 μg of elcatonin (Reference Example 2 preparation). Comparative Example 1 In the same manner as in Reference Example 2 above, lactic acid or a sodium salt thereof was used as various monocarboxy compounds or salts thereof, and a glass ampoule that had not been subjected to the alkali removal treatment as in Reference Example 2 was used. Using the same, an aqueous solution of elcatonin shown in Table 1 was obtained, and an injection containing 7 μg of elcatonin was produced in the same manner (Comparative 1 formulation). Comparative Example 2 In the same manner as in Reference Example 2 above, citric acid or a sodium salt thereof is used as each of the various polyvalent carboxy compounds or salts thereof, and the same alkali removal treatment as in Reference Example 2 has not been performed. Using an ampoule, an aqueous solution of elcatonin shown in Table 1 was obtained, and an injection containing 7 μg of elcatonin was produced in the same manner (Comparative 2 formulation). Reference Examples 3 to 5 In the same manner as in Reference Example 1 or Reference Example 2, various monocarboxy compounds and polyvalent carboxy compounds or salts thereof may be used as L-histidine hydrochloride (Reference Example 3), succinic acid An aqueous solution of elcatonin shown in Table 1 was obtained using sodium (Reference Example 4), sodium tartrate (Reference Example 5), and an untreated glass ampoule in the same manner as in Reference Example 2. Thus, an injection containing 7 μg of elcatonin was produced (Reference Example 3, Preparation 4, and Reference Example 5). [Table 1] Test Example 1 Elcatonin injections containing the various aqueous elcatonin compositions obtained in each of the Examples, Comparative Examples and Reference Examples were placed in a paper box, and shaken in a thermostatic shaking machine to stabilize them. The property was measured by high performance liquid chromatography, and the residual ratio was determined. The results are shown in Table 2. Shaking conditions Amplitude: 10 cm Number of times of shaking: 120 times / min Temperature: 25 ° C. High performance liquid chromatography Measurement conditions Column: ODS column 4.6 × 150 mm Detection: UV 220 nm Mobile phase: CH ₃ CN-0.1% TFA (34: 66) [Table 2] The thus obtained elcatonin preparation of the present invention has the composition shown in Table 1 above, and as is clear from Table 2 showing the residual ratio of the preparation after elapse of the shaking time, the elcatonin preparation The fact that the composition of the pH buffer solution in Example 1 was so low that the pH fluctuation was likely to occur in a normal glass ampule was improved, and the effect of improving the stability by using a dealkalized glass ampule was recognized. Test Example 2 In the preparation of the pH 5.5, 0.1 mM sodium acetate pH buffer obtained in Reference Example 1, four kinds of solutions were adjusted so that the concentration of sodium chloride was 3 mM, 10 mM, 154 mM, and 500 mM. Prepared. Elcatonin was dissolved at 7 μg / milliliter and filled in ampoules in the same manner as in Reference Example 1 to produce elcatonin injections having four ionic strengths. The obtained elcatonin injection was stored at 45 ° C. for 3 months, and the residual ratio was determined under the measurement conditions performed in Test Example 1. Table 3 shows the results. [Table 3] As shown in Table 3, the elcatonin injection having an ionic strength of 0.01 to 0.500 was stable as a result of a severe heat test. Similarly, instead of sodium acetate, pH 5.5, 0.1 mM sodium lactate (composition based on Example 1),
At pH 5.5, 20.0 mM L-histidine hydrochloride (composition based on Reference Example 3), the concentration of sodium chloride was adjusted to 3 mM, 10 mM, 154 mM, and 500 mM.
The following four solutions were prepared in the same manner as described above.
The storage stability at 5 ° C. for 3 months was observed at an ionic strength of 0.01 to 0.5 as in the case of sodium acetate. As described above, according to the present invention, an alkali-treated glass container is filled with an aqueous solution of elcatonin to form an elcatonin preparation, which is prepared using an untreated container. A more stable preparation can be obtained as compared with an elcatonin preparation, and by selecting a monocarboxy compound or a water-soluble salt thereof, a pH value, and an ionic strength, the preparation is particularly stable against shaking and heat, and is light-resistant. And a stable and favorable elcatonin preparation can be provided.

Claims (1)

Claims: 1. An alkali-treated borosilicate glass ampoule container having a pH of 5.0 .
Lactate buffer or p with 0-6.5 and Ionic Strength Agency μ = 0.01-0.5
A stable elcatonin preparation filled with an aqueous solution composition containing elcatonin as an active ingredient, which contains a citric enzyme buffer having an H of 5.5 and an ionic strength of μ = 0.15 . 2. A stable elcatonin preparation according to claim 1, wherein the aqueous composition is an injectable composition.