JPH07179359A - Stable elcatonin preparation - Google Patents

Abstract

PURPOSE:To obtain the subject elcatonin preparation useful as an injection, having stability to shaking, heat and light by packing an aqueous solution composition comprising elcatonin as an active ingredient to a container made of glass subjected to alkali removal treatment. CONSTITUTION:This preparation is obtained by packing an aqueous solution composition (preferably a composition for injection having pH of 5.0-6.5 and of ionic strength (mu) 0.01-0.5) comprising elcatonin [chemical name: 1-butyric acid-7-(L-2-aminobutyric acid)-26-L-aspartic acid-27-L-valine-29-L-alaninecalcitonin (salmon)] as an active ingredient into a container made of glass (preferably ampule or a container made of vial glass) subjected to alkali removal treatment, for example, by bringing an aqueous solution of ammonium sulfate into contact with an inner wall of the container, heating and then cleaning the container by ultrasonic wave.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stable elcatonin preparation in which a dealkalized glass container is 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 a
cid) -26-L-aspartic acid-27-L-valine-29-L-alanineca
lcitonin (salmon)] is a drug used for improving pain in hypercalcemia, Paget's disease of bone, or osteoporosis.

[0003]

When this drug is used as an aqueous solution formulation, the activity of elcatonin may be reduced by vigorous shaking, so that the drug does not always have satisfactory stability as a formulation considering stability against shaking. It wasn't good. Conventionally, in the present situation that the mechanism of activity reduction due to shaking of aqueous peptide solutions is not fully clarified, the present inventors have taken the above problems into consideration, and, in view of the above problems, the present inventors have overcome the thermal stability as an injection. ， Light stability,
The aim was to maintain the current state of pain reduction during inoculation into the human body or to improve it further.Also, it was reported that the solution of the activity decrease due to shaking of the aqueous peptide solution by adding a surfactant has been reported. From the aspect of the above, there was a problem in that, and intensive studies were conducted to maintain good activity of elcatonin even without the addition of a surfactant.

[0004]

Therefore, the present inventors have
In an aqueous solution composition containing elcatonin as an active ingredient,
Surprisingly, in an injection container, which is a glass container for medical use such as an ampoule or a vial used for filling an aqueous solution composition containing elcatonin as an active ingredient, an aqueous solution composition containing elcatonin as an active ingredient in a dealkalized glass container. It was found that a stable elcatonin preparation can be obtained by filling the product. Furthermore, it has been found that a more stable and stable elcatonin preparation can be obtained when the pH of this elcatonin aqueous solution composition is 5.0 to 6.5 and the ionic strength is μ = 0.01 to 0.5.

The present invention has been made based on the above findings, that is, the present invention relates to a stable elcatonin preparation in which a dealkalized glass container is filled with an aqueous solution composition containing elcatonin as an active ingredient. First, the main production method of an aqueous solution composition containing elcatonin as an active ingredient of the present invention is, for example, in an aqueous solution composition containing elcatonin as an active ingredient, pH 5.0 to 6.5 and ionic strength μ = 0.0.
An effective amount of elcatonin may be dissolved in an aqueous medium of 1 to 0.5 to prepare an elcatonin aqueous solution composition such as elcatonin injection solution. At this time, a monocarboxy compound such as acetic acid, lactic acid or L-histidine or , Succinic acid, polyvalent carboxy compounds such as tartaric acid and citric acid and / or their water-soluble salts, for example sodium salts, may be used as buffering agents, and such monocarboxy compounds, polyvalent carboxy compounds and / or them The water-soluble salt may be prepared at an appropriate molar concentration, preferably 0.05 to 20 mmol, and particularly preferably the monocarboxy compound or its sodium salt is adjusted to a concentration of 0.05 to 20 mmol. It was prepared by Moreover, in preparing the elcatonin aqueous solution composition, in detail, with a buffer solution containing a monocarboxy compound or a polyvalent carboxy compound and / or a water-soluble salt thereof, the pH is adjusted, and the ionic strength thereof is calculated, If necessary, non-toxic strong electrolyte inorganic salts such as sodium chloride and potassium chloride are added to obtain an aqueous medium with adjusted ionic strength, and it is easy to dissolve an effective amount of elcatonin as an active ingredient, It may be dissolved in an effective amount of elcatonin at the stage of the preparation of the aqueous medium of interest appropriately, does not necessarily specify the order of preparation, and isotonic agent, which is another formulation component, if necessary, Soothing agents, stabilizers, absorption enhancers, preservatives and the like can be added. In particular, a buffer containing a monocarboxy compound and / or a water-soluble salt thereof,
A buffer solution containing a monocarboxy compound and / or a water-soluble salt thereof which can be medically added, and the final composition has a pH of 5.
It suffices if it has a buffering action capable of maintaining the range of 0 to 6.5. Further, medically addable monocarboxy compounds or salts thereof are organic compounds having one carboxyl group in the molecule or salts thereof, such as acetic acid, lactic acid, L-histidine or salts thereof sodium acetate, lactic acid. Preferred embodiments include sodium, potassium acetate, potassium lactate, and L-histidine hydrochloride.

In these monocarboxy compounds and / or salts thereof, one or more kinds of these may be used, or acetic acid and / or a water-soluble salt thereof such as sodium salt and potassium salt may be appropriately mixed and used, This is pH 5.
The pH is adjusted to 0 to 6.5, and the pH may be finely adjusted with sodium hydroxide, hydrochloric acid or the like, if necessary. p
The amount of H buffer used depends on the pH of the elcatonin aqueous solution composition.
Can be a minimum amount to buffer 5.0 to 6.5, and when the composition is used as an injection, the amount used (as a 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 adjusted as necessary by adding sodium chloride, potassium chloride or the like so that the ionic strength is μ = 0.01 to 0.5. Can be mentioned, and μ = 0.04 to
A preferable mode is to adjust to 0.3. μ = 1/2 Σr _i · z _i ² (r _i : molar concentration of ions, z
_i : its ionic value) When sodium chloride, potassium chloride, etc. are added, the amount used is, for example, preferably 0.2 to 1.2%.

The effective content of the active ingredient, elcatonin, is usually 1 to 100 μg per milliliter of the solution.
It is usually 1 to 10 μg per milliliter of solution in the case of injection, and usually 1 to 100 μg per milliliter of solution in the case of nasal preparation. The aqueous solution of elcatonin thus obtained is injected into a glass container for pharmaceutical parenteral administration such as ampoule or vial and filled and filled with an aqueous solution injection or the nasal solution of the aqueous solution by a conventional method. It can be made into a preparation such as a main agent for administration. In particular, since the pH buffer solution of the elcatonin aqueous solution composition is diluted, pH fluctuation is likely to occur in an ordinary glass ampoule, and for example, in an ampoule or a vial container formed of borosilicate glass or soda lime glass. When brought into contact with each other, pH fluctuation occurs due to external factors such as elution of an alkaline component from the surface of the glass container, which causes fluctuation of pH of the elcatonin aqueous solution composition.

In such a case, a method of selectively washing and removing the alkaline component on the surface of the glass container, for example, 2
By contacting the glass surface with a water-soluble sulfur oxide such as sulfurous acid gas or ammonium sulfate at a high temperature of about 50 to 800 ° C., the alkaline component on the surface becomes fine sulfate crystals,
After that, using a dealkalized processed container to be washed, that is, using a dealkalized glass container according to the present invention, by a conventional method, injection and filling may be performed in consideration of an appropriate effective amount of the above elcatonin aqueous solution composition. .

The formulation for parenteral administration comprising a dealkalized glass container filled with the thus obtained elcatonin aqueous solution composition improves the stability of elcatonin, and particularly has a molar concentration of 0.05 to 20. Using millimolar monocarboxy compound or its water-soluble salts,
Is 5.0 to 6.5 and the ionic strength is μ = 0.01 to 0.5.
The preparations obtained by the method of (1) have particularly good stability against shaking and heat of elcatonin, and also the light stability as an injectable agent and the reduction of pain during inoculation into the human body, which have been overcome in the past. It was an excellent formulation that was as good as the product.

[0011]

EXAMPLES The present invention will be described below with reference to examples.
The present invention is not limited to these examples, comparative examples or reference examples.

[0012]

Example 1 Sodium acetate (trihydrate) 0.544
g, and 1.8 g of sodium chloride are dissolved in water to obtain a solution of 200 ml.
Diluted to 200 ml with 9% (w / v) sodium chloride solution. Add 0.002N hydrochloric acid to 0.7
The mixture was added with milliliter and mixed to adjust the pH to 5.5 and the ionic strength to 0.15. Solution 20 thus obtained
Dissolve 1.4 mg of elcatonin in 0 ml,
An elcatonin aqueous solution composition was obtained.

Since the pH buffer solution of the elcatonin aqueous solution composition is diluted, the pH tends to fluctuate in an ordinary glass ampoule. Therefore, a dealkalized ampoule (0.5% ammonium sulfate aqueous solution is applied to the inner wall surface of the ampoule). Contact, heat at about 600 ° C., then ultrasonically clean, wash with distilled water for injection, and dry at 250 ° C.), and use 1 ml of the alkali-treated glass ampoule containing 1 ml of the elcatonin aqueous solution composition. Thus, an injection containing 7 μg of elcatonin was produced (Example 1
Formulation). The operations in the following Examples, Comparative Examples and Reference Examples were performed aseptically.

[0014]

Example 2 Various monocarboxy compounds and / or lactic acid or its sodium salt was used as the salt thereof in the same manner as in Example 1 above, and a dealkalized glass ampoule similar to Example 1 was used. The aqueous elcatonin composition shown in 1 was obtained, and an injection containing 7 μg of elcatonin was produced in the same manner (Example 2 formulation).

[0015]

Example 3 In the same manner as in Example 1 above, various polyvalent carboxy compounds and / or citric acid or its sodium salt was used as its salt, and the same dealkalized glass ampoule as in Example 1 was used. Then, the aqueous elcatonin composition shown in Table 1 was obtained, and an injection containing 7 μg of elcatonin was produced in the same manner (Example 3 formulation).

[0016]

[Comparison 1] The following comparison will be given as a comparison with the first embodiment. 0.544 g of sodium acetate (trihydrate),
Sodium chloride (1.8 g) was dissolved in water to obtain a 200 ml solution, which was designated as solution A. Separately 0.24 acetic acid
g and 1.8 g of sodium chloride are dissolved in water to obtain a solution of 200 ml, which is referred to as solution B. To 200 ml of A liquid, 25 ml of B liquid was added and mixed, and p
It was adjusted to H5.5 and ionic strength of 0.17.

Elcatonin (1.4 mg) was dissolved in 200 ml of the thus obtained solution to obtain an elcatonin aqueous solution composition. Next, 1 ml each of this elcatonin aqueous solution composition was filled into a 1 cc glass ampoule (without dealkalization treatment) to give 7 μg of elcatonin.
Was prepared (comparatively 1 formulation).

[0018]

[Comparative Example 2] In the same manner as in Comparative Example 1 above, various monocarboxy compounds and / or lactic acid or its sodium salt was used as a salt thereof, and a glass ampoule similar to Comparative Example 1 which had not been treated with dealkalization was used. Using the same, an elcatonin aqueous solution composition shown in Table 1 was obtained, and elcatonin 7 was similarly prepared.
Injections containing μg were prepared (2 proportional formulations).

[0019]

[Comparative Example 3] In the same manner as in Example 1, a glass ampoule using various monocarboxy compounds and / or citric acid or a sodium salt thereof as a salt thereof and having not undergone dealkalization treatment similar to Comparative Example 1 was used. Was used to obtain an elcatonin aqueous solution composition shown in Table 1, and an injection containing 7 μg of elcatonin was produced in the same manner (comparative 3 formulations).

[0020]

[Reference Example 1] In the same manner as in Example 1 or Comparative Example 1, L-histidine hydrochloride (Reference Example 1 preparation), sodium succinate (as various monocarboxy compounds and polyvalent carboxy compounds and / or salts thereof) Reference Example 2 preparation), sodium tartrate (Reference Example 3 preparation), and proportional 1
Using the same glass ampoule not subjected to the dealkalization treatment described above, an elcatonin aqueous solution composition shown in Table 1 was obtained, and an injection containing 7 μg of elcatonin was produced in the same manner (Reference Example 1 formulation).

[0021]

[Table 1]

[0022]

[Test Example 1] Elcatonin injections containing the various elcatonin aqueous solution compositions obtained in each Example, Comparative Example and Reference Example were placed in a paper box and shaken in a constant temperature shaker to stabilize at high speed. It was measured by liquid chromatography to determine the residual rate. The results are shown in Table 2. Shaking conditions Amplitude: 10 cm Shaking frequency: 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: 6
6)

[0023]

[Table 2]

The elcatonin preparation of the present invention thus obtained has the composition shown in Table 1 above, and as is clear from Table 2 showing the residual rate of the preparation after the shaking time,
Since the composition of the pH buffer solution in the elcatonin formulation is dilute, it was found that the ordinary glass ampoule was liable to cause pH fluctuation, and the stability improving effect was observed by using the dealkalized glass ampoule. .

[0025]

[Test Example 2] In the preparation of 0.1 mM sodium acetate pH buffer at pH 5.5 obtained in Example 1, the concentration of sodium chloride was 3 mM, 10 mM, 154 mM, 500 mM.
Four kinds of solutions were prepared so that Elcatonin was dissolved in this to 7 μg / ml and the ampoule was filled in the same manner as in Example 1 to prepare an elcatonin injection having four kinds of ionic strength. The obtained elcatonin injection was stored at 45 ° C. for 3 months, and the residual rate was determined under the measurement conditions used in Test Example 1. The results are shown in Table 3.

[0026]

[Table 3]

As shown in Table 3, the ionic strength is 0.01
Elcatonin injections of ˜0.500 were stable as a result of the heat severe test. Similarly, instead of sodium acetate, pH 5.5, 0.1 mM sodium lactate (composition according to Example 2), pH 5.5, 20.0 mM
With L-histidine hydrochloride (composition based on Reference Example 1), the sodium chloride concentration was 3 mM, 10 mM,
Four kinds of solutions were prepared so that the concentrations were 154 mM and 500 mM, and the same procedure was followed to prepare 45 of elcatonin injection.
The storage stability at 3 ° C. for 3 months was observed at an ionic strength of 0.01 to 0.5 as in the case of sodium acetate.

[0028]

As described above, according to the present invention,
By filling an elcatonin aqueous solution composition into a dealkalized glass container to form an elcatonin formulation, a more stable formulation can be obtained as compared to an elcatonin formulation prepared using an untreated container, and a monocarboxy compound Alternatively, by selecting a water-soluble salt thereof, a pH value, and an ionic strength, it is possible to provide a good elcatonin preparation which is particularly stable to shaking and heat and stable to light.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area A61K 9/08 G 47/12 J 47/18 J

Claims (4)

[Claims] 1. A stable elcatonin preparation in which a dealkalized glass container is filled with an aqueous solution composition containing elcatonin as an active ingredient. 2. The pH of the aqueous solution composition is 5.0 to 5.0.
The stable elcatonin preparation according to claim 1, which has a ionic strength of 6.5 and μ = 0.01 to 0.5. 3. The stable elcatonin preparation according to claim 1, wherein the dealkalized glass container is an ampoule or a vial glass container. 4. The stable elcatonin preparation according to claim 1, wherein the aqueous solution composition is an injectable composition.