JPH0892102A - Injection containing bisphosphonic acid or derivative therefrom and method for stabilizing the injection and injection ampul - Google Patents

Abstract

PURPOSE: To obtain a bisphosphonic acid injection relatively stable with little quality deterioration even after storage, containing a bisphosphonic acid or a derivative therefrom, organic acid buffering agent and, if desired, an isotonicizing agent and/or aminoalcohol. CONSTITUTION: This injection contains, as active ingredient, a bisphosponic acid or a derivative therefrom of formula I (R and R<1> -R<4> are each H or an alkyl; (n) us 3-10) or formula II (R<5> and R<6> are each H or an alkyl), containing an organic acid buffering agent ingredient (pref. citric acid, tartaric acid or lactic acid as the organic acid ingredient) and, if desired, an isotonicizing agent (e.g. sodium chloride, polyhydric alcohol) and/or aminoalcohol. This injection is relatively stable, deteriorating little even after long-term storage or storage under severe conditions. It is preferable that the concentration of the buffering ingredient stand at 1-250mM. The pH level of this injection is pref. 3.5-5.5.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an injection solution containing bisphosphonic acid or a derivative thereof as an active ingredient, a method for stabilizing the same, and an injection solution ampoule.

[0002]

2. Description of the Related Art With respect to bisphosphonic acid or its derivatives, it has been known for a long time that bone resorption and an increase in serum calcium level associated with the enhancement of bone resorption are suppressed, and the enhancement of bone resorption has an important role in the pathological condition. It has already been introduced into therapeutic practice as an agent in drugs for treating diseases that are believed to occur, such as Paget's disease, hypercalcemia, bone metastases of cancer, osteoporosis. By the way, when a bisphosphonic acid or a derivative thereof is prepared in an injection solution and stored in a glass ampoule and stored, a relatively long storage period elutes aluminum ions and the like in the glass composition due to erosion of the glass ampoule over time. Therefore, there are problems that the injection solution is suspended, the active substance content is decreased, and the aluminum content is increased.

In order to cope with such an adverse effect, international patent application WO94 / 0 has been proposed as a technique for suppressing aluminum ions eluted from a glass ampoule and stabilizing an injection solution.
The invention described in No. 5297 is known. A feature of the present invention is that the pH value of the injection solution is adjusted to about 3.0 to 4.5, and / or the injection solution contains polyethylene glycol, and the glass ampoule optionally subjected to surface heat treatment is filled. Thus, the bisphosphonic acid or its derivative can be filled in a glass ampoule as a stable injection solution.

[0004]

However, in the invention described in the above-mentioned international patent application WO94 / 05297, sufficient consideration is not given to thermal stability,
Stable storage is difficult under thermally harsh conditions. In addition to stabilizing the injection solution itself, it is possible to more effectively prevent the elution of aluminum ions and the like, which causes the increase of insoluble foreign substances in the injection solution, even in the glass ampoule filled and stored. In addition, it is an important issue to improve the stability of the bisphosphonic acid so that the stability of the bisphosphonic acid is maintained even in the presence of aluminum ions. The present invention has been made in view of these problems, and is more stable, and a bisphosphonic acid injection solution which is less deteriorated even during long-term storage or storage under severe conditions, a method for stabilizing the same, and an injection solution ampoule. The purpose is to provide.

[0005]

According to the present invention, a bisphosphonic acid or a derivative thereof, and an organic acid buffer component are contained, and if desired, a tonicity agent and / or an amino alcohol is further contained. A stable bisphosphonic acid injection solution is provided. Further, according to the present invention, bisphosphonic acid or a derivative thereof is blended with an organic acid buffer component, and if desired, isotonicity agent and / or amino alcohol is further blended to stabilize the bisphosphonic acid injection solution. A method is provided. Further according to the invention,
There is provided an injection solution ampoule obtained by filling the above-mentioned bisphosphonic acid injection solution into a glass ampoule having a silicon oxide film formed on its inner surface.

The present invention will be described in detail below. In the present invention, the organic acid buffer component refers to an organic acid having a pharmaceutically acceptable buffering ability. Examples of the acid component that constitutes the organic acid buffer include citric acid, tartaric acid, succinic acid, maleic acid, malic acid, gluconic acid and its alkali metal salts, lactic acid and the like. Of these, citric acid, tartaric acid, and lactic acid are preferable. By blending these organic acid buffer components, the thermal stability is improved, the complex formation with aluminum ions eluted from the glass ampoule is suppressed, and the generation of insoluble foreign substances in the injection solution is suppressed. The organic acid buffer component is added so that the concentration thereof is 0.5 mM or more, and the range is up to the upper limit of the amount of each pharmaceutical additive used once or per day. Concentration is 1-250mM
Is preferably added so that the concentration becomes 5 to 200 mM, and more preferably 5 to 200 mM. Further, the more the added amount of the organic acid buffer component is, the more stable the bisphosphonic acid can be maintained.

Further, the bisphosphonic acid injection solution of the present invention is
Further, it may contain a tonicity agent and / or an amino alcohol, if desired. Here, the isotonicity agent means a pharmaceutically acceptable isotonicity agent, and sodium chloride, polyhydric alcohol and the like are usually used. As polyhydric alcohol,
Examples thereof include sugar alcohols such as D-mannitol, D-sorbitol, inositol, and meglumine, and glycerin and propylene glycol, and it is preferable to use one or more selected from these. In addition, examples of the amino alcohol include monoethanolamine, diethanolamine, triethanolamine and the like, and it is preferable to use one or more selected from these. In particular, D-mannitol and glycerin can be preferably used because they have not only an isotonic effect but also an effect of suppressing the generation of insoluble fine particles when blended in an injection solution. The amount of the isotonicity agent and / or aminoalcohol to be added is such that the osmotic pressure ratio becomes a value that is acceptable as an injection, and specifically, a bolus or an infusion.
In the use mode of n) (continuous intravenous injection such as infusion), an amount in which the osmotic pressure ratio is about 0.5 to 3 is preferable, and an amount in which the osmotic pressure ratio is about 0.8 to 2 is more preferable. In order to obtain a more stable bisphosphonic acid injection solution, one or more organic acid buffer components selected from the group consisting of citric acid, tartaric acid and lactic acid, and a group consisting of D-mannitol, meglumine, and glycerin It is preferable to add one or more tonicity agents selected from the above.

The pH of the injectable solution is usually adjusted to about 3.0 to 6.0, but from the viewpoint of long-term stability, it is 3.5 to 5.5.
Is preferable, and it is more preferable that it is 4.0 to 5.0. The bisphosphonic acid or its derivative contained in the injectable solution as the active ingredient of the present invention is not particularly limited. For example, European Patent Application EP0170228,
EP0197478, EP0222471, EP0
252504, EP0252505, EP0258
618, EP0350002, EP0273190
And international patent application WO 90/00798. Further, hydrates and solvates of these bisphosphonic acids or their derivatives can be used as well. Among such bisphosphonic acids or derivatives thereof, (cycloalkylamino) methylenebis (phosphonic acids) represented by the following general formula (1) described in JP-A-1-308290, lower alkyl esters thereof or physiologically acceptable thereof Salt and JP-A-2-138
The heterocyclic bisphosphonic acid derivative lower alkyl ester represented by the following general formula (2) described in JP-A No. 288 or a physiologically acceptable salt thereof is mentioned as a preferable example, and particularly preferable one is (cycloheptylamino). ) Methylenebis (phosphonic acid) monohydrate and 1-hydroxy-2- (imidazo [1,2-a] pyridine-3-
Il) ethane-1,1-bis (phosphonic acid) disodium monohydrate can be mentioned.

[0009]

[Chemical 1]

[0010]

[Chemical 2]

In preparing the injection solution of the present invention,
First, an amount of a sodium hydroxide solution (for example, 0.01 N or more) capable of dissolving a predetermined amount of bisphosphonic acid or its derivative.
1N) is added. After dissolution, an organic acid buffer is added and, if desired, a tonicity agent and / or amino alcohol is added, and then the pH is adjusted. The thus-obtained injection solution is usually filled in a glass ampoule made of borosilicate glass and stored, and as a glass ampoule used at this time, it causes increase of insoluble foreign substances in the injection solution. In order to prevent elution of metal ions and the like in the glass composition, it is preferable that the inner surface be subjected to some treatment. According to the experiments conducted by the present inventors, it was found that the use of an ampoule having a silicon oxide film formed on the inner surface surprisingly improves the stability and significantly suppresses the generation of insoluble foreign matters. After filling the injection solution, it is preferable that the glass ampoule space portion be closed while being replaced with nitrogen. In addition, a pharmaceutically acceptable solubilizing agent, usually during the production of an injection,
A soothing agent, a preservative, an antioxidant, and a surfactant may be added.

[0012]

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

Example 1 and Comparative Example : Compound A (1-hydroxy-2- (imidazo [1,2-a] pyridine-3-
Yl) ethane-1,1-bis (phosphonic acid) monohydrate) as 1-hydroxy-2- (imidazo [1,2-a]
100 mg of pyridin-3-yl) ethane-1,1-bis (phosphonic acid) was weighed, and a sodium hydroxide solution was added to dissolve the compound A. After dissolution, various buffers shown in Table 1 were added so that the final concentration reached the value shown in the same table, pH was adjusted with a solution of hydrochloric acid or sodium hydroxide, and water for injection was added to bring the total volume to 200 ml. And This solution was filtered through a membrane filter having a pore size of 0.22 μm, filled in a glass ampoule, and a conventional (untreated) glass ampoule space part made of borosilicate glass was melted while being replaced with nitrogen. This was autoclaved at 115 ° C. for 30 minutes to obtain injection solutions of sample numbers 1 to 25 shown in Table 1. In order to evaluate the stability of the injection solution thus obtained, it was stored at 60 ° C. for 2 weeks and 4 weeks, the residual rate of the active ingredient, Compound A, was determined, and the thermal stability was examined. The results are shown in Table 1.

[0014]

[Table 1]

As is clear from the results shown in Table 1, the injection solutions using citric acid, tartaric acid and lactic acid as sample Nos. 1 to 22 had a residual rate of Compound A of 60% at 90 ° C. for 4 weeks. It was found to be high and excellent in stability. On the other hand, it was found that the injection solutions using acetic acid as the buffer of Sample Nos. 24 to 25 had a low residual rate of Compound A of 88.5% or less when stored at 60 ° C. for 4 weeks, and lacked stability. Further, when citric acid, tartaric acid, and lactic acid were used as the organic acid buffer component, the stability was good at pH 3.0 to 6. However, it was found that the injection solution using citric acid as the buffer of Sample No. 23 had a high pH value of 7 and therefore had a low residual rate of Compound A and lacked stability.

Example 2 : Compound A (1-hydroxy-2
-(Imidazo [1,2-a] pyridin-3-yl) ethane-1,1-bis (phosphonic acid) monohydrate) was converted into 1-hydroxy-2- (imidazo [1,2-a] pyridine. -3
-Yl) ethane-1,1-bis (phosphonic acid)
100 mg was weighed and a sodium hydroxide solution was added to dissolve the compound A. After dissolution, various buffer agents shown in Table 2 were added so that the final concentrations would be the values shown in the same table, and various isotonic agents, aminoalcohols, etc. shown in the same table were added as additives. It was added so that the concentration became the value shown in the table. Then pH with a solution of hydrochloric acid or sodium hydroxide
Was adjusted, and water for injection was further added to make the total volume 200 ml. This solution was filtered through a membrane filter having a pore size of 0.22 μm, and then filled into a normal (untreated) glass ampoule made of borosilicate glass, and the space inside the glass ampoule was replaced with nitrogen to be sealed. This was autoclaved at 115 ° C. for 30 minutes to obtain injection solutions of sample numbers 26 to 70 shown in Table 2. In order to evaluate the stability of the injection solutions of Sample Nos. 26 to 66 among them, they were stored at various temperatures and for a period of time, inspected for insoluble fine particles, and the residual rate of Compound A as an active ingredient was measured. The results are shown in Tables 3 to 5.

Also, the material of the ampoule and the presence or absence of surface treatment,
In order to carry out a comparative study of the stability by the surface treatment method, the injection solution of Sample No. 26 was filled in various ampoules and stored,
Similarly, the insoluble fine particles were inspected and the residual rate was measured.
The ampoule used was a normal (untreated) glass ampoule made of borosilicate glass, a glass ampoule with a silicone resin applied on the inner surface (silicon coat ampoule), and an acid treatment with ammonium sulfate etc. on the inner surface. A glass ampoule from which components have been removed (sulfur-treated ampoule), a glass ampoule having a silicon oxide film formed on its inner surface (silicon oxide-coated ampoule), and a plastic container. The results are shown in Table 6.
Shown in.

In the present example, the insoluble fine particles were inspected by using the method by the light blocking method and the method by the ampoule inspector from the following viewpoints. That is, generally, as a method of insoluble foreign matter inspection for injections, the measurement of visible foreign matter such as the first method defined by the Japanese Pharmacopoeia is known, but before the detection by this test method, insoluble foreign matter is detected under more severe conditions. Tracking the occurrence is the mission of those who supply safe medications to the human body. Therefore, a method using a light blocking method (automatic particle measuring device using the light blocking method: HIAC / manufactured by Leuco) or irradiating a strong white light beam from the lower part of the ampoule and rotating the ampoule to easily find a foreign substance The method (ampoule tester method) is often used as a more stringent foreign material test method. The method based on the light block method is also described in USP (US Pharmacopoeia), and has various advantages such as easy test and quantification of the amount of foreign substances. Moreover, the method using an ampoule tester can be actually confirmed by human eyes, and it seems that these two measurement methods have a considerable correlation.

[0019]

[Table 2]

[0020]

[Table 3]

[0021]

[Table 4]

[0022]

[Table 5]

[0023]

[Table 6]

As can be seen from the results of Tables 3 to 5, citric acid and tartaric acid were used as buffering agents, and a tonicity agent and / or
Alternatively, it was found that the injection solution containing a predetermined amount of amino alcohol complies with the Japanese Pharmacopoeia Method 1 of the insoluble foreign matter test method, in which the generation and presence of insoluble fine particles are small and there is no problem in practical use. Also, as is clear from the results in Table 6,
It has been found that a container using a silicon oxide-coated ampoule or a plastic container as a container for filling and storing an injection solution is extremely preferable because there is almost no generation or existence of insoluble fine particles.

Example 3 : Compound B ((cycloalkylamino) methylenebis (phosphonic acid) disodium monohydrate) was used as (cycloalkylamino) methylenebis (phosphonic acid) disodium, 125 mg was weighed, and added to 200 ml of water for injection. Dissolved. Lactic acid 1.2 after dissolution
g and 2.25 g of sodium chloride were added and dissolved, the pH was adjusted with a solution of sodium hydroxide (about 4.9), and water for injection was further added to bring the total volume to 250 ml. This solution is aseptically filtered and then usually (untreated) made from borosilicate glass
The glass ampoule of No. 2 was filled with the glass ampoule and the space inside the glass ampoule was closed by nitrogen replacement. This was autoclaved at 115 ° C. for 30 minutes to obtain an injection solution.

In order to evaluate the stability of the injectable solution thus obtained, it was stored at 40 ° C. for 6 months and tested according to the insoluble foreign matter test method No. 1 etc. stipulated in the General Rules for Preparations of the Japanese Pharmacopoeia. . As a result, the injection solution complies with the Japanese Pharmacopoeia Method 1 of the insoluble foreign matter test, and the residual rate of Compound B is 10 or less.
It was 0%. Therefore, it was confirmed that the compound B was practically useful, with little deterioration even during long-term storage or storage under heat-harsh conditions.

[0027]

As described above, in the present invention, an injection solution containing bisphosphonic acid or a derivative thereof is mixed with an organic acid buffer component, and if desired, a tonicity agent and / or amino alcohol is mixed. By providing a stable bisphosphonic acid injection solution that improves thermal stability, suppresses the formation of a complex with aluminum ions eluted from the glass ampoule, and suppresses the generation of insoluble foreign substances in the injection solution. You can Therefore, the thus-stabilized injection solution of the present invention shows little deterioration even during long-term storage or storage under thermally harsh conditions and is extremely useful in practice. Further, by storing the injection solution of the present invention in a glass ampoule having a silicon oxide film formed on its inner surface, the stability is further improved and the generation of insoluble foreign matter is significantly suppressed.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Harue Totsuka 1008 Yokouchi, Fujieda City, Shizuoka Prefecture

Claims (13)

[Claims] 1. A stable bisphosphonic acid injection solution containing bisphosphonic acid or a derivative thereof and an organic acid buffer component, and further optionally containing a tonicity agent and / or an amino alcohol. 2. The bisphosphonic acid injection solution according to claim 1, wherein the acid component constituting the organic acid buffer is one or more selected from the group consisting of citric acid, tartaric acid and lactic acid. 3. The organic acid buffer component has a concentration of 0.5 mM.
The bisphosphonic acid injection solution according to claim 1 or 2, which is added as described above. 4. The organic acid buffer component has a concentration of 1 to 250.
The bisphosphonic acid injection solution according to claim 3, which is added so as to be mM. 5. The bisphosphonic acid injection solution according to claim 1, wherein the tonicity agent is a polyhydric alcohol. 6. The polyhydric alcohol is one or more selected from the group consisting of sugar alcohols D-mannitol, D-sorbitol, inositol and meglumine, and propylene glycol and glycerin. Bisphosphonic acid injection solution. 7. The bisphosphonic acid injection solution according to claim 1, wherein the amino alcohol is one or more selected from the group consisting of monoethanolamine, diethanolamine and triethanolamine. 8. The bisphosphonic acid injection solution according to claim 1, wherein the injection solution has a pH value of 3.0 to 6.0. 9. The bisphosphonic acid injection solution according to claim 1, wherein the pH value of the injection solution is 3.5 to 5.5. 10. A bisphosphonic acid or a derivative thereof, one or more organic acid buffer components selected from the group consisting of citric acid, tartaric acid and lactic acid, and a group consisting of D-mannitol, meglumine and glycerin. A bisphosphonic acid injection solution containing one or more selected isotonicity agents. 11. A bisphosphonic acid or its derivative is
(Cycloheptylamino) methylenebis (phosphonic acid), or 1-hydroxy-2- (imidazo [1,2-
The bisphosphonic acid injection solution according to claim 1 or 10, which is a] pyrimidin-3-yl) ethane-1,1-bis (phosphonic acid) or a physiologically acceptable salt. 12. A method for stabilizing a bisphosphonic acid injection solution, which comprises adding an organic acid buffer component to bisphosphonic acid or a derivative thereof, and further adding an isotonicity agent and / or an amino alcohol, if desired. 13. An injection ampoule obtained by filling the bisphosphonic acid injection solution according to any one of claims 1 to 11 into a glass ampoule having a silicon oxide film formed on its inner surface.