JPH07277967A - Aqueous calcium preparation for oral administration and its preparation - Google Patents

Abstract

PURPOSE:To provide an aqueous calcium preparation for oral administration, causing little precipitation of insoluble calcium salt even at a high calcium concentration, having safety and preservable for a long period. CONSTITUTION:This aqueous preparation is produced by preparing an aqueous solution containing (a) >3.33W/V% and <=15 W/V% of calcium gluconate and (b) 6-40W/V% of D-sorbitol at a ratio especially satisfying the formula (b):((a)-3.33)>=2.1 wherein (a) and (b) are contents of the components (a) and (b), respectively, and compounding the aqueous solution with (c) citric acid at <=55 deg.C. As necessary, the product is sterilized at <=90 deg.C after the compounding of citric acid (c).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oral calcium aqueous preparation and a method for producing the same, and more particularly to an oral calcium aqueous preparation which contains calcium at a high concentration and has almost no precipitation of insoluble calcium salt and can be stored for a long period The manufacturing method is related.

[0002]

2. Description of the Related Art The daily amount of calcium required for adults is
It is said to be around 600 mg, but due to recent changes in eating habits, the amount of calcium ingested by Japanese people is decreasing, and it is rare for people to ingest 600 mg of calcium per day only in their diet. . When this calcium deficiency becomes remarkable, it may cause osteoporosis. In addition, pregnant women and young children should take a larger amount of calcium. Therefore, in order to supplement the deficiency of calcium as described above, foods containing a large amount of calcium are commercially available, but in these foods, there is a problem that the taste deteriorates as the content of calcium increases. .
Further, as pharmaceutical calcium preparations, solid preparations such as powders, granules, tablets, dragees, and capsules are provided, but these have a problem that the dosage is large as a solid preparation and the absorption rate is low. is there.

Accordingly, oral calcium aqueous preparations containing a calcium organic acid salt having a high absorption rate have come to the forefront, and particularly, the storage stability is good, and the solubility in water is high, so that a high concentration calcium aqueous solution can be prepared. A variety of products using easy calcium lactate have come to be sold. However, the calcium lactate has a peculiar bitterness and further has a problem of poor residual taste. For this reason, sweeteners and grapefruit essences have been added, but it is not possible to completely mask the bitterness and the like, and therefore calcium-based lactate-containing calcium-based formulations are shunned by consumers. There is a problem that there is a tendency.

Therefore, calcium gluconate, which is a tasteless and odorless calcium organic acid salt, has come to be used as a calcium source. However, oral calcium aqueous preparations have been instructed by the Pharmaceutical Manufacturing Guidelines (National Regulations of the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare) that the daily intake of calcium should be 300 mg to 700 mg. Calcium has a solubility of 3.
Since it is as low as 33 g / 100 ml, in order to take more than 300 mg of calcium from the saturated solution of calcium gluconate, it is necessary to take a little less than 90 ml a day, and if calcium is not continuously taken, Since it is not possible to expect an effect, for example, if you sell 10 to 15 days as one product unit,
There is a problem that the container largely deviates from the general size range of drugs. Therefore, by adding an organic acid such as citric acid or a polyhydric alcohol such as D-sorbitol to the aqueous calcium preparation, calcium gluconate can be dissolved at a concentration twice or more its solubility. The aqueous solution of calcium gluconate has a problem that calcium ions are chemically extremely unstable and calcium salts are likely to precipitate or become cloudy. Therefore, various oral calcium-based aqueous preparations in which such precipitation and turbidity of calcium gluconate are suppressed have been proposed. Japanese Unexamined Patent Publication No. 1-268638 discloses calcium gluconate 3 to 10 W / V%, benzoic acid.
Disclosed is an aqueous calcium solution agent containing 0.01 to 0.1 W / V%, common salt 0.01 to 0.1 W / V% and citric acid, and having a pH adjusted to 3 to 5. Further, JP-A-2-212 discloses that one or more organic acids selected from water-soluble polyhydric alcohols having 12 or less carbon atoms, lactic acid, calcium gluconate and ascorbic acid, 0.4 W / V% or more calcium ions and 0.
Disclosed is an oral aqueous preparation containing 1 W / V% or more of magnesium ion and optionally a water-soluble polymer compound such as polyethylene glycol for preventing the precipitation of calcium salt.

[0005]

However, the oral calcium aqueous preparation described in JP-A-1-268638 does not cause precipitation or turbidity at room temperature, but is sterilized at high temperature or stored at low temperature. For example, since it is not possible to sufficiently cope with the change in the solubility due to the change in the liquid temperature, there is a problem that precipitation is likely to occur with the change in the temperature condition. Further, since the oral calcium aqueous preparation described in JP-A-2-212 contains a large amount of a water-soluble polymer compound such as polyethylene glycol in order to prevent the formation of precipitates, it depends on the temperature conditions. There is a problem in that the viscosity changes and also causes foaming, which causes inconvenience in the manufacturing process. Moreover, the solubility of calcium gluconate in water at room temperature is more than twice that of 3.33 g / 100 ml, for example, 8.4 g / 1.
If it is a highly concentrated solution with a supersaturation of 00 ml, it is enough to take about 40 ml to ingest 300 mg in terms of calcium,
When 500 ml of the oral aqueous calcium preparation is sold as a bottle, it is stored for 12.5 days or longer. However, since the oral calcium aqueous preparations described in JP-A-1-268638 and JP-A-2-212 do not always have sufficient stability of calcium ions, they are stored in a low temperature environment such as a refrigerator. There is a problem that precipitates and turbidity tend to occur as the period of time increases.

By the way, the oral calcium-based preparation is
Organic acid salts such as citrates, carbonates and tartrates, especially citrates are often added as buffers, pH adjusters, stabilizers and flavors. Also, calcium gluconate is
As mentioned above, it has been reported that at high concentrations, it becomes chemically unstable and undergoes an ionic reaction with organic acid salts such as citrate, carbonate, tartrate, etc. to precipitate calcium salts with each organic acid. [(Aoki Dai: Pharmacy 24,3
31 (1964)]. The calcium salt of the organic acid, such as calcium citrate, is often sparingly soluble or insoluble in water, and it is extremely difficult to redissolve the precipitate once formed. Further, since many oral calcium-based aqueous preparations have a pH value on the acidic side, and the acidic component is likely to be liberated due to pH fluctuation due to mixing, the above tendency is more remarkable.

[0007] Therefore, the present inventors have explained the reason why calcium gluconate and citrate react with each other in the oral calcium aqueous preparation containing calcium gluconate and citrate to cause precipitation of calcium citrate. As a result of diligent research, as disclosed in Japanese Patent Laid-Open No. 1-268638, citric acid was previously dissolved in purified water heated to 80 to 90 ° C., and calcium gluconate was dissolved in the citric acid to dissolve the glucone. An oral calcium aqueous preparation containing calcium acid and citric acid is produced, but by allowing citric acid and calcium gluconate to coexist in such a high temperature state, an ionic reaction occurs between citric acid and calcium gluconate. It was found that the above phenomenon occurred and a precipitate was easily generated. It was also found that precipitates are more likely to occur depending on the sterilization temperature and sterilization time in the sterilization process of the calcium-based aqueous preparation.

The present invention has been made on the basis of the above problems, and provides an oral calcium aqueous preparation which contains calcium at a high concentration, has almost no precipitation of insoluble calcium salts, and is safe and can be stored for a long period of time. With the goal. Another object of the present invention is to provide a method for producing an oral calcium aqueous preparation which contains calcium in a high concentration, has almost no precipitation of insoluble calcium salt, and can be stored safely for a long period of time.

[0009]

The oral calcium aqueous preparation according to claim 1 of the present invention comprises (a) calcium gluconate.
It contains more than 3.33 W / V% and 15 W / V% or less and (b) D-sorbitol 6 to 40 W / V%, and the content ratio of (a) and (b) is (b): ((a ) −3.33) ＝ 2.1 or more is satisfied.

Further, the method for producing an oral calcium aqueous preparation according to claim 2 of the present invention is (a) calcium gluconate
More than 3.33 W / V% and 15 W / V% or less, (b) D-sorbitol 6-40 W / V%, (c) Citric acid 0.1-2 W / V%
A method for producing an oral calcium aqueous preparation containing: (a) preparing an aqueous solution of calcium gluconate (b) D-sorbitol, and adding (c) citric acid to the aqueous solution at 55 ° C. or lower. To do.

Furthermore, the method for producing an oral calcium aqueous preparation according to claim 3 is 90% after the above-mentioned (c) citric acid is blended.
Sterilize at ℃ or below.

The present invention will be described in detail below.

[1] Oral calcium aqueous preparation First, the oral calcium aqueous preparation of the present invention will be explained. The oral calcium aqueous preparation of the present invention contains (a) calcium gluconate and (b) D-sorbitol as essential components.

In the present invention, (a) calcium gluconate has the following chemical formula: [CH ₂ OH—CH (OH) ₄ —COO ⁻ ] ₂ Ca ^2+.
It is generally represented by H ₂ O, has a molecular weight of 448.39, and may contain a trace amount of the above structure without water of crystallization. In the oral calcium aqueous preparation of the present invention, the lower limit of the content of (a) calcium gluconate is more than 3.33 W / V%. When the calcium gluconate is 3.33 W / V% or less, the solubility at room temperature (20 ° C., the same applies below) is 3.33 W / V%, so that precipitation due to calcium gluconate does not occur. The lower limit of the content of calcium gluconate is preferably 5 W / V% or more, particularly preferably 8 W / V% or more. If the content of calcium gluconate is less than 5 W / V%, precipitation due to calcium gluconate is unlikely to occur, and the effect of blending D-sorbitol is not remarkable. Further, if the content of calcium gluconate is less than 8 W / V%, the amount of the calcium aqueous preparation for ingesting 300 mg of calcium per day becomes large, which is not preferable. Further, the upper limit of the content of calcium gluconate is 15 W / V% or less. If the content of calcium gluconate exceeds 15 W / V%, its dissolution is difficult. The content of calcium gluconate as described above is preferably about 8.4 W / V%. By setting the calcium gluconate content to about 8.4 W / V%, 1
The required amount of the aqueous calcium preparation for ingesting 300 mg or more of calcium per day can be set to about 40 ml, and for example, the above-mentioned amount of calcium can be ingested by taking 20 ml each twice a day, which is easy to take. However, there is almost no precipitation of calcium when stored at 0 ± 1 ° C. for a long period of time, for example, 14 days.

In the present invention, (b) D-sorbitol is a non-reducing monosaccharide generally used as a sweetener, and in the present invention, it acts as a crystallization inhibitor of calcium gluconate. The D-sorbitol has the following chemical formula: CH ₂ OH—CH (OH) ₄ —.
It is common to have 1/2 or 1 molecule of water of crystallization in what is represented by CH ₂ OH. Such D-sorbitol can be obtained by reducing glucose. The lower limit of the content of D-sorbitol as described above is 6 W / V% or more. 6 calcium gluconates
If it is less than W / V%, precipitation tends to occur in the content rate of calcium gluconate. The content of D-sorbitol is preferably 8 W / V% or more, particularly preferably 10 W / V% or more. When the D-sorbitol content is less than 8 W / V%,
If the effect of preventing the precipitation of calcium is not sufficient and the content of D-sorbitol is less than 10 W / V%, the precipitation of calcium when the content of calcium gluconate is increased to more than twice the solubility at room temperature It is not preferable because the prevention effect is not sufficient. In addition, the upper limit of the D-sorbitol content is 40 W / V% or less. When the content of D-sorbitol exceeds 40 W / V%, not only the effect of preventing the precipitation of calcium further can be obtained, but also the viscosity of the oral calcium aqueous preparation is increased. Preferred D
-The content of sorbitol is 20 W / V% or less. Even if the content of D-sorbitol exceeds 20 W / V%, it is not economical because a corresponding effect of preventing precipitation of calcium cannot be obtained. The content of D-sorbitol as described above is about 15
Most preferably it is W / V%. By setting the content rate of D-sorbitol to about 15 W / V%, even when the content rate of calcium gluconate is increased to more than twice the solubility at room temperature, a sufficient calcium precipitation preventing effect can be obtained. You can

However, in the present invention, the content ratio of (a) calcium gluconate and (b) D-sorbitol as described above satisfies (b): ((a) -3.33) = 2.1 or more. is there. The present inventors have found that it is surprising that the content of D-sorbitol satisfying the above formula significantly suppresses the formation of precipitates due to calcium gluconate present in supersaturation. . In the formula, (a) indicates the content rate of calcium gluconate (unit: W / V%), (b) indicates the content rate of D-sorbitol (unit: W / V%), and 3.33 indicates that at room temperature. It shows the solubility of calcium gluconate (unit: g / 100 ml). That is, the above formula defines the ratio of D-sorbitol to the content exceeding the solubility of calcium gluconate at room temperature. (B):
If ((a) -3.33) is less than 2.1, the effect of preventing precipitation of calcium cannot be obtained even if the content of calcium gluconate and D-sorbitol is within the above range. Preferred (b): The value of ((a) -3.33) is 2.60 or more.
(B): When the value of ((a) -3.33) is less than 2.60, a sufficient calcium precipitation preventing effect cannot be obtained. It is particularly preferably 2.90 or more. (B): The value of ((a) -3.33) is 2.
When it is 90 or more, calcium hardly precipitates even if it is stored for 14 days or more, for example, 17 days under the condition of 0 ± 1 ° C. The upper limit of the value of (b): ((a) -3.33) is not particularly limited, but it is preferably 40 or less, particularly 20 or less.

The oral calcium aqueous preparation of the present invention contains (a) calcium gluconate and (b) D-sorbitol as essential components. Various ingredients to
For example, it may contain an organic acid, a polyhydric alcohol, paraoxybenzoic acid esters, a flavoring agent and the like.

The organic acid is added as a pH adjuster, and citric acid, tartaric acid, malic acid or the like can be used. Of these, citric acid is particularly preferable. The content of the organic acid can be appropriately set within a range in which the pH of the oral calcium aqueous preparation can be adjusted to 3 to 6, preferably 3.5 to 5.0. For example, in the case of citric acid
It is preferably 0.1 to 2 W / V%. If the citric acid content is less than 0.1 W / V%, the pH of the oral calcium aqueous preparation cannot be within the above range, while if the citric acid content exceeds 2 W / V%, Not only can the pH of the oral calcium aqueous preparation not fall within the above range, but also the precipitation of calcium citrate tends to occur, as will be described later. Particularly preferred citric acid content is 0.1-1 W /
V%. When the content of citric acid exceeds 1 W / V%,
Not only is it difficult to keep the pH of the oral calcium aqueous preparation within the above range, but also calcium citrate easily precipitates, which is not preferable.

The polyhydric alcohol is added in order to help prevent the formation of (a) calcium gluconate precipitates, and polyethylene glycol, propylene glycol, polyvinylpyrrolidone, polyvinyl alcohol or the like can be used. . Of these, propylene glycol is particularly preferable. The content of the propylene glycol is usually 0.05 to 5 W / V%, preferably 0.1.
~ 3 W / V%.

The paraoxybenzoic acid esters mainly act as a preservative, and ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, or derivatives thereof can be used. Of these, paraoxybenzoic acid is preferred. The paraoxybenzoic acid ester is, for example, 0.01
Add about 0.1 W / V%.

Further, a flavoring agent can be added to the oral calcium aqueous preparation of the present invention. As the flavoring agent, amino acids and nucleic acids such as glycine, aspartic acid, glutamic acid or salts thereof can be used. Among these, 1- which is a salt of glutamic acid
Sodium glutamate is preferred. A small amount of the flavoring agent may be added.

The oral calcium aqueous preparation of the present invention comprises:
If necessary, various other components that can be usually added to an oral calcium aqueous preparation, such as a flavoring agent such as lemon essence and grapefruit essence, a coloring agent such as riboflavin, and a thickening agent can be added.

The oral calcium aqueous preparation of the present invention comprising various components as described above can be produced by a conventional method. For example, an organic acid such as citric acid is added to thermally purified water heated to 80 ° C or higher, then calcium gluconate and D-sorbitol are dissolved, and the resulting aqueous solution is heated to 40 ° C.
It can be manufactured by cooling to a certain degree, dissolving various additives, cooling to room temperature, and then adding purified water so that each component has a desired concentration. However, when the oral calcium aqueous preparation of the present invention contains (c) citric acid in addition to (a) calcium gluconate and (b) D-sorbitol, a reaction purified product of citric acid and calcium gluconate. In order to prevent the precipitation of calcium citrate, it is preferable to produce an oral calcium aqueous preparation by the method of the present invention as described below.

[2] Method for Producing Oral Calcium Aqueous Formulation Next, a method for producing the oral calcium aqueous formulation of the present invention will be described. The method for producing an oral calcium aqueous preparation of the present invention includes (a) calcium gluconate exceeding 3.33 W / V% and 15 W / V% or less, and (b) D-sorbitol 6 to 40 W /.
This is a method for producing an oral calcium aqueous preparation containing V% and (c) 0.1 to 2 W / V% citric acid. The contents of (a) calcium gluconate and (b) D-sorbitol and the reasons for limiting the contents are the same as in the case of the above-mentioned oral calcium aqueous preparation. That is, the lower limit of the content rate of calcium gluconate is 3.
It is more than 33 W / V%, preferably 5 W / V% or more, particularly preferably 8 W / V% or more. The upper limit is 15 W / V% or less, and the content of calcium gluconate is preferably about 8.4 W / V%. The lower limit of (b) D-sorbitol content is 6 W /
V% or more, preferably 8 W / V% or more, particularly preferably 10
W / V% or more, and the upper limit is 40 W / V% or less, preferably 20 W / V% or less. In addition, in the above-described oral calcium aqueous preparation of the present invention, the content ratio of (a) calcium gluconate and (b) D-sorbitol was defined as (b): ((a) -3.33) = 2.1 or more. In the method for producing an oral calcium aqueous preparation of the present invention, the method is not limited to this, but (b):
((A) -3.33) = 2.1 or more, especially 2.60 or more, and 2.
It is preferably 90 or more.

The content of (c) citric acid is 0.1-2.
W / V%. If the content of citric acid is less than 0.1 W / V%, the pH of the oral calcium aqueous preparation cannot be within the above range, while the content of citric acid is 2 W / V%.
If it exceeds the above range, not only the pH of the above-mentioned oral calcium aqueous preparation cannot be adjusted within the above range but also precipitation of calcium citrate is likely to occur as described later. The preferable citric acid content is 0.1 to 1 W / V%. When the content of citric acid exceeds 1 W / V%, it is not preferable because it is difficult to keep the pH of the above-mentioned oral calcium aqueous preparation within the above range and calcium citrate easily precipitates.

Other polyhydric alcohols, paraoxybenzoic acid esters, flavors, fragrances, colorants, etc.
Thickeners and the like can be added as necessary.

Next, a method for producing an oral calcium aqueous preparation containing each of the above components will be described. First, an aqueous solution of calcium gluconate and D-sorbitol is prepared. The adjustment of the aqueous solution is, for example, 80 to
Dissolve a specified amount of calcium gluconate in 100 ° C hot purified water. It is preferable that the calcium gluconate is dissolved so as to have a content slightly higher than a desired content. The calcium gluconate may be added to the hot purified water all at once, but it is preferable to add the calcium gluconate over about 1 hour while confirming the dissolution little by little. Next, when the calcium gluconate is completely dissolved, D-sorbitol is added. Thereafter, when a polyhydric alcohol such as propylene glycol or ethyl paraoxybenzoate is added, it is dissolved. The liquid temperature at this time is preferably 80 ° C. or lower in order to prevent oxidization and denaturation of propylene glycol. The thus obtained solution containing calcium gluconate and D-sorbitol was heated to a liquid temperature of 55.
Allow to cool to below ℃. Then, a predetermined amount of citric acid is added to this solution. When the liquid temperature at the time of blending the citric acid exceeds 55 ° C., citric acid and calcium gluconate react with each other to produce calcium citrate.
In particular, the liquid temperature is preferably 50 ° C. or lower. When the liquid temperature exceeds 55 ° C., citric acid and calcium gluconate react with each other to easily generate calcium citrate. The lower limit of the liquid temperature of the aqueous solution may be a temperature at which the solution does not freeze, but it is usually room temperature or higher. Further, at this stage, it is preferable to add a flavoring agent such as sodium l-glutamate and a flavoring agent such as lemon essence, if necessary. The citric acid, sodium 1-glutamate, lemon essence and the like can be added at one time, but it is preferable to add them after completely confirming their dissolution one by one. Purified water is added to the aqueous solution obtained as described above to adjust the calcium gluconate to a predetermined concentration. In addition,
Each component other than calcium gluconate also has a desired concentration by addition of the purified water by adding a slight excess of the final concentration according to the amount of calcium gluconate in the initial purified water. You can The thus obtained oral calcium aqueous preparation is filtered once or twice or more as necessary to remove precipitating impurities and the like. After that, it is preferable to perform sterilization if necessary. The sterilization is an oral calcium-based formulation
It is usually carried out by heating to about 120 ° C. and holding, but in the present invention, it is carried out by holding at 90 ° C. or lower. This is because, when sterilization is performed at a temperature higher than 90 ° C., calcium ions stabilized in the dissolution step are activated again and react with citric acid to generate calcium citrate. The preferred sterilization temperature is 75-90 ° C. If the sterilization temperature is less than 75 ° C, a sufficient sterilization effect cannot be obtained. The heating and holding time at the sterilization temperature is
In order to prevent the formation of calcium citrate, it is preferable that the length be short, but it may be appropriately set according to the sterilization temperature. For example, if the sterilization temperature is 90 ° C, 60 minutes or less, 85 ° C, 90 minutes or less, 80 minutes or less.
The temperature is preferably 120 minutes or less. The oral calcium-based preparation thus obtained can be put on the market by filling it in a bottle or the like. As the bottle body, for example, one having a capacity of about 500 ml may be used. The oral calcium aqueous preparation obtained by the method of the present invention as described above hardly causes precipitation of calcium citrate even when it is stored at low temperature for a long time.

In the method for producing an oral calcium aqueous preparation of the present invention as described in detail above, the contents of (a) calcium gluconate and (b) D-sorbitol are (b): ((a) −3.33) = 2.1 When the above relation is satisfied, the advantages of the above-described oral calcium aqueous preparation of the present invention can be obtained, which is particularly preferable. In other words, it is possible to provide an ideal oral calcium-based pharmaceutical preparation that does not generate a precipitate due to calcium gluconate from its manufacturing process to sterilization and storage for a long period of refrigeration.

[0029]

In the oral calcium aqueous preparation according to claim 1, (a) calcium gluconate and (b) D-sorbitol are contained in predetermined amounts, and the content ratio of (a) and (b) is Since the ratio is within the predetermined range, precipitation due to supersaturation of calcium gluconate does not occur even after long-term storage. Although the reason why such an effect is obtained is not always clear, in the present invention, the amount of (a) calcium gluconate is set to be larger than its solubility in water at room temperature. It is considered that the crystallization of calcium gluconate is remarkably suppressed by setting the content of (b) D-sorbitol within the specific range with respect to the calcium gluconate exceeding 10%.

Further, in the method for producing an oral calcium aqueous preparation according to claim 2, precipitation of calcium does not occur even when calcium gluconate is at a high concentration. The reason why such an effect is obtained is not necessarily clear, but as a result of diligent studies on the reason why the present inventors tend to cause precipitation in an oral calcium aqueous preparation containing calcium gluconate and citric acid, the above-mentioned precipitation It was found that the product was mainly calcium citrate. Therefore, the present inventors further studied the reason why the calcium citrate is produced, and an oral calcium aqueous preparation containing calcium gluconate and citric acid was found to contain citric acid in purified water heated to 80 ° C. or higher. Is dissolved in advance, and it is produced by dissolving calcium gluconate therein. Therefore, by allowing citric acid and calcium gluconate to coexist in such a high temperature state, an ionic reaction occurs between citric acid and calcium gluconate. It was found that this is due to the reaction between calcium gluconate and citric acid. From the above findings, first, an aqueous solution of (a) calcium gluconate and (b) D-sorbitol is prepared, and the aqueous solution is kept at 50 ° C. or lower and (c) citric acid is added to the solution to obtain (a) gluconic acid. It is presumed that this is because it is possible to stabilize calcium ions caused by calcium.

Further, in the method for producing an oral calcium aqueous preparation according to claim 3, since (c) citric acid is blended and sterilized at 90 ° C. or lower, calcium citrate is added even after sterilization. No precipitation occurs.

[0032]

The present invention will be described in more detail by the following specific examples.

Examples 1 to 13 and Comparative Examples 1 to 10 About 80 ml of purified water heated above 80 ° C (about 85 ° C),
8.4 g of (a) calcium gluconate (Ca-Glu) was mixed, stirred and dissolved, and then (b) D-sorbitol (D-Sor) in the weight shown in Table 1 and Table 2 was mixed and dissolved. did. This aqueous solution was allowed to cool to room temperature (about 20 ° C.) and then purified water was added to make the total volume 100 ml. The aqueous calcium preparation for oral administration thus obtained was filtered using a membrane filter, transferred to a glass container, stoppered, and sterilized at 85 ± 3 ° C. for 30 minutes. After cooling, open the cap and add this oral calcium aqueous preparation to 0 ± 1 ° C.
The amount of precipitation was visually observed at the initial stage, after 1 day, after 3 days, after 6 days and after 14 days. The results are shown in Tables 3 and 4. Comparative Example 1 is a case of using purified water alone. Also, in Tables 3 and 4, the precipitation amount was visually confirmed by observing the volume of the precipitation which was 100% when the precipitation was generated in the total amount of 100 ml of the oral calcium aqueous preparation. None ±: Precipitation amount less than 1% +: Precipitation amount 1 to less than 10% (hereinafter, “+” per one increase in volume of about 10% precipitation). The value of (b): ((a) -3.33) in each oral calcium aqueous preparation was calculated. The results are also shown in Tables 1 and 2.

[0034]

[Table 1]

[0035]

[Table 2]

[0036]

[Table 3]

[0037]

[Table 4]

As is clear from Tables 1 to 4, (a)
At a calcium gluconate content of 8.4 W / V%,
(B) The content rate of D-sorbitol is (b): ((a)-
3.33) = 2.4 or more, the oral calcium aqueous preparations of Examples 1 to 13 had less than 1% of the precipitate due to calcium gluconate even after storage at 0 ± 1 ° C. for 14 days. In particular,
(B): ((a) -3.33) = 2.1 or more Example 6-
13 oral calcium aqueous preparations, 0 ± 1 ℃
No precipitation occurred even after storage for 14 days. In contrast, the oral calcium aqueous preparations of Comparative Examples 2 to 5 in which D-sorbitol was less than 6 W / V% had a remarkably large amount of precipitate. Moreover, since the oral calcium aqueous preparations of Comparative Examples 6 to 10 had (b): ((a) -3.33) = less than 2.4, a precipitate had already formed after 6 days of storage.

Examples 14 and 15 and Comparative Examples 11 to 19 About 80 ml of purified water heated above 80 ° C. (about 90 ° C.),
Mix 13.0 g of (a) calcium gluconate and stir
It was dissolved, and then (b) D-sorbitol in the weight shown in Table 3 was blended and dissolved. After the aqueous solution was left to cool to room temperature, purified water was added to make the total volume 100 ml. The aqueous calcium preparation for oral administration thus obtained was filtered using a membrane filter, transferred to a glass container, stoppered, and sterilized at 85 ± 3 ° C. for 30 minutes. After cooling, the container was opened and stored, and the aqueous calcium preparation for oral use was stored at 0 ± 1 ° C., and the amount of precipitation was observed in the same manner as in Example 1 at the initial stage, 1 day, 3 days, 6 days, and 14 days later. The results are shown in Table 6. (B) in each oral calcium aqueous preparation:
The value of ((a) -3.33) was calculated. The results are also shown in Table 5. Comparative Example 11 is a case of using purified water alone.

[0040]

[Table 5]

[0041]

[Table 6]

As is clear from Tables 5 and 6,
(A) Even when the concentration of calcium gluconate was extremely high at 13.0 W / V%, the oral calcium aqueous preparations of Examples 14 and 15 were precipitated due to calcium gluconate even after storage at 0 ± 1 ° C. for 14 days. Was less than 1%. Especially (b):
((A) −3.33) = 3.29 In the oral calcium aqueous preparation of Example 15 having the above values, no precipitation occurred even after storage at 0 ± 1 ° C. for 14 days. In contrast, the oral calcium aqueous preparations of Comparative Examples 12 to 19 had remarkably large amounts of precipitates.

Examples 16 to 18 and Comparative Examples 20 to 27 About 80 ml of purified water heated above 80 ° C (about 90 ° C),
The weight of (a) calcium gluconate shown in Table 7 was mixed, stirred and dissolved, and then 15.0 g (b) D-sorbitol was mixed and dissolved. After the aqueous solution was left to cool to room temperature, purified water was added to make the total volume 100 ml. The aqueous calcium preparation for oral administration thus obtained was filtered using a membrane filter, transferred to a glass container, stoppered, and sterilized at 85 ± 3 ° C. for 30 minutes. After cooling, the container was opened and stored, and this oral calcium aqueous preparation was stored at 0 ± 1 ° C., and the amount of precipitation was observed in the same manner as in Example 1 at the initial stage, 1 day, 3 days, 8 days, and 17 days. The results are shown in Table 8. The value of (b): ((a) -3.33) in each oral calcium aqueous preparation was calculated. The results are shown in Table 7.
It is shown together with. Comparative Example 20 is a case of using purified water alone.

[0044]

[Table 7]

[0045]

[Table 8]

As is clear from Tables 7 and 8,
(B) Under the condition of D-sorbitol concentration of 15.0 W / V%, (a) the concentration of calcium gluconate is (b):
((A) −3.33) = 2.4 or more The oral calcium aqueous preparations of Examples 16 to 18 did not cause precipitation due to calcium gluconate even after storage at 0 ± 1 ° C. for 8 days. Particularly, (b): ((a) −3.33) = 2.1 or more Example 1
0 ± 1 for 6 and 17 oral aqueous calcium preparations
No precipitation occurred even after storage for 17 days at ℃. In contrast, in the oral calcium aqueous preparations of Comparative Examples 22 to 27, precipitation occurred by the 8th day.

Examples 19-23 To approximately 80 ml of purified water heated above 80 ° C (about 85 ° C),
Mix 8.4 g of (a) calcium gluconate and stir
It was dissolved, and then 15 g of (b) D-sorbitol was blended and dissolved. This aqueous solution was left at room temperature and cooled to 60 ° C or lower, and then ethyl paraben 0.012 was added to propylene glycol.
0.3g of propylene glycol equivalent solution
After addition, the mixture was allowed to stand at room temperature and cooled to 50 ° C or lower,
0.01 g sodium glutamate and 0.4 g citric acid,
A small amount of fragrance was added, and the mixture was stirred and dissolved, and after cooling to room temperature, purified water was added to 100 ml in total. The oral aqueous calcium preparation thus obtained was filtered using a membrane filter and then transferred to a glass container,
Cap and sterilize at 85 ± 3 ℃ for 30 minutes. After cooling, this oral calcium aqueous preparation was stored at the temperature shown in Table 5, and the amount of precipitation was observed after 3 days, 1 week, 3 months, 6 months and 8 months, and the same procedure as in Example 1 was performed. evaluated. The results are shown in Table 9 and Table 10.

[0048]

[Table 9]

[0049]

[Table 10]

As is clear from Tables 9 and 10, the oral calcium aqueous preparation of the present invention did not cause precipitation even after being stored for 8 months under various temperature conditions.
Neither turbidity nor the like was observed.

Production Examples of Oral Calcium Aqueous Formulation Examples 24-32 and Comparative Examples 28-54 Approximately 160 ml of purified water heated to 80-96 ° C. was mixed with 16.8 g of calcium gluconate (a). Stir and dissolve,
Next, the liquid temperature was adjusted to the temperatures shown in Tables 11 and 12, various amounts of citric acid were dissolved, and purified water at the above temperature was added to this to make the total amount 200 ml. The aqueous calcium preparation for oral administration thus obtained was kept at the dissolution temperature of citric acid in a water bath, and the time until the insoluble calcium salt was precipitated was measured. The results are shown in Table 11 and Table 12. The measurement test was carried out for up to 240 hours, and those in which precipitation did not occur during this period were "abnormal".

[0052]

[Table 11]

[0053]

[Table 12]

As is clear from Tables 11 and 12, those without addition of citric acid (addition amount 0 W / V%) do not produce precipitates at any temperature, but among those with addition of citric acid, In the method for producing an oral calcium aqueous preparation of Comparative Examples 29 to 31, 33 to 35, 37 to 39, 41 to 43, 45 to 47 and 49 to 51, the temperature of which exceeds 55 ° C when citric acid is added, precipitation occurs. Occurred. Particularly, when the addition temperature of citric acid was abnormal at 80 ° C, precipitation occurred within 30 minutes. On the other hand, in the method for producing the oral calcium aqueous preparation of each example, no precipitation was observed even after 240 hours. From these facts, this precipitate is expected to be calcium citrate. In addition, the calcium ion in the aqueous solution is 55 ℃
It is considered that the following temperatures hardly react with citric acid.

Examples 33-35 and Comparative Examples 55, 56 Approximately 80 ml of purified water heated above 80 ° C (about 85 ° C),
Mix 8.4 g of (a) calcium gluconate and stir
It was dissolved, and then 15 g of (b) D-sorbitol was blended and dissolved. This aqueous solution was left at room temperature and cooled to 60 ° C or lower, and then ethyl paraben 0.012 was added to propylene glycol.
0.3g of propylene glycol equivalent solution
After adding and standing at room temperature and cooling to 50 ° C, 0.4 g of citric acid was dissolved and 0.01 g of sodium l-glutamate was added.
Then, a small amount of fragrance was added, and the mixture was stirred and dissolved. After cooling to room temperature, purified water was added to 100 ml in total. After filtering the oral calcium aqueous preparation thus obtained using a membrane filter, it was transferred to a glass container, stoppered and sterilized at the temperature shown in Table 13, until a precipitate was formed. The time was measured. The results are also shown in Table 13.

Comparative Examples 57-61 About 80 ml of purified water heated to 80 ° C. or higher (about 85 ° C.),
Citric acid (0.4 g) was dissolved, then 8.4 g (a) calcium gluconate was mixed, stirred and dissolved, and further 15 g (b) D-sorbitol was mixed and dissolved. This aqueous solution is left at room temperature and cooled to 60 ° C or lower, then 0.3 g of a solution of 0.012 g of ethylparaben in propylene glycol is added in terms of propylene glycol, further left at room temperature and cooled to 50 ° C, and then l -0.01 g of sodium glutamate and a trace amount of fragrance were added, stirred and dissolved, cooled to room temperature, and purified water was added to 100 ml in total. After filtering the oral calcium aqueous preparation thus obtained using a membrane filter, it was transferred to a glass container, stoppered and sterilized at the temperature shown in Table 13, until a precipitate was formed. The time was measured. The results are also shown in Table 13.

[0057]

[Table 13]

As is clear from Table 13, the sterilization temperature is 90 ° C.
In the method for producing an oral calcium aqueous preparation of Examples 33 to 35 and Comparative Examples 59 to 61, which are as follows, the time until the formation of precipitates is higher than that in the production method of Comparative Examples 55 to 58 in which the sterilization temperature exceeds 90 ° C. It was short. In addition, Examples 33 to 35 and Comparative Examples 59 to
Comparative example in which citric acid was added at 80 ° C or higher even between 61
It can be seen that in 59 to 61, the time until the formation of precipitates is significantly shorter than in Examples 33 to 35.

Example 36 About 80 ml of purified water heated above 80 ° C. (about 85 ° C.),
Mix 8.4 g of (a) calcium gluconate and stir
It was dissolved, and then 15 g of (b) D-sorbitol was blended and dissolved. This aqueous solution was left at room temperature and cooled to 60 ° C or lower, and then ethyl paraben 0.012 was added to propylene glycol.
0.3g of propylene glycol equivalent solution
After adding and standing at room temperature and cooling to 50 ° C, 0.4 g of citric acid was dissolved and 0.01 g of sodium l-glutamate was added.
Then, a small amount of fragrance was added, and the mixture was stirred and dissolved. After cooling to room temperature, purified water was added to 100 ml in total. The oral calcium aqueous preparation thus obtained was filtered using a membrane filter, transferred to a glass container, left at 85 ± 3 ° C for 30 minutes, and cooled to room temperature (20
℃), 40 ℃, left at -1 ℃, immediately after production, 12 hours later, 24
The amount of precipitate was visually observed after hours, 1 month and 6 months. The results are shown in Tables 14 and 15. The room temperature (20 ° C) may be left in a room having a temperature of 1 to 30 ° C.

Comparative Example 62 About 80 ml of purified water heated above 80 ° C. (about 85 ° C.)
Citric acid (0.4 g) was dissolved, then 8.4 g (a) calcium gluconate was mixed, stirred and dissolved, and further 15 g (b) D-sorbitol was mixed and dissolved. This aqueous solution is left at room temperature and cooled to 60 ° C or lower, then 0.3 g of a solution of 0.012 g of ethylparaben in propylene glycol is added in terms of propylene glycol, further left at room temperature and cooled to 50 ° C, and then l -0.01 g of sodium glutamate and a trace amount of fragrance were added, stirred and dissolved, cooled to room temperature, and purified water was added to 100 ml in total. The thus obtained oral calcium aqueous preparation was filtered using a membrane filter, transferred to a glass container, left at 85 ± 3 ° C for 30 minutes, and cooled at room temperature (20 ° C), After standing at 40 ° C. and −1 ° C., the amount of precipitate was visually observed immediately after production, 12 hours, 24 hours, 1 month, and 6 months. The results are shown in Tables 14 and 15.

[0061]

[Table 14]

[0062]

[Table 15]

As is clear from Tables 14 and 15, the Examples
According to the method for producing 36 orally calcium-based aqueous preparations, no precipitation occurred even after 6 months at any of room temperature, 40 ° C. and −1 ° C. On the other hand, according to the production method of Comparative Example 62, a precipitate was rapidly formed after 12 hours. Incidentally, the precipitation in Comparative Example 62 is 1 to according to the notation.
Although it is less than 10%, it is about 1 to 3%.

[0064]

The oral calcium aqueous preparation according to claim 1 of the present invention comprises (a) calcium gluconate exceeding 3.33 W / V% and 15 W / V% or less, and (b) D-sorbitol 6 to 40 W /.
V% and the contents of (a) and (b) are (b):
Since ((a) −3.33) = 2.1 or more is satisfied,
Precipitation, turbidity, etc. do not occur even if calcium gluconate is contained in a high concentration.

The method for producing an oral calcium aqueous preparation according to claim 2 of the present invention is (a) calcium gluconate 3.
Production of an oral calcium aqueous preparation containing more than 33 W / V% and 15 W / V% or less, (b) D-sorbitol 6-40 W / V%, and (c) citric acid 0.1-2 W / V% In the method, an aqueous solution of (a) calcium gluconate and (b) D-sorbitol is prepared, and (c) citric acid is added to the aqueous solution at 55 ° C. or lower. Almost no calcium citrate, which is a reaction product of the above, is produced.

Furthermore, in the method for producing an oral calcium aqueous preparation according to claim 3, since (c) citric acid is mixed and sterilized at 90 ° C. or lower, calcium citrate is added after sterilization. No precipitation of the main component occurs.

Claims (3)

[Claims] 1. A) calcium gluconate 3.33 W / V%
Above 15 W / V% and (b) D-sorbitol 6-
An oral calcium aqueous preparation containing 40 W / V%, wherein the contents of (a) and (b) satisfy (b): ((a) -3.33) = 2.1 or more. 2. (a) Calcium gluconate 3.33 W / V%
Above 15 W / V% and (b) D-sorbitol 6-
In the method for producing an oral calcium aqueous preparation containing 40 W / V% and (c) citric acid 0.1 to 2 W / V%, an aqueous solution of (a) calcium gluconate and (b) D-sorbitol is prepared. And (c) citric acid is added to the aqueous solution at 55 ° C. or lower, to prepare an oral calcium aqueous preparation. 3. After blending the (c) citric acid, 90 ° C.
The method for producing an oral calcium aqueous preparation according to claim 2, wherein sterilization treatment is performed below.