JP3776334B2 - Inulin-containing preparation - Google Patents

Description

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【発明の効果】
本発明のイヌリン含有製剤は、イヌリンが分解したり、製剤が黄変することもなく、イヌリンの安定性が著しく改善されたものである。腎機能の把握に用いられる糸球体濾過量の測定に有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a stable pharmaceutical preparation containing inulin useful as a diagnostic agent.
[0002]
[Prior art]
An inulin preparation is used for the measurement of glomerular filtration rate performed for confirming the progress of symptoms of a renal disease patient, but the inulin preparation has significant improvements in resolubility and stability. Due to defects in re-solubility, production efficiency and use in the medical field are extremely poor, so it was listed in the BP 1968 Addendum 1969 in the United Kingdom, and also in the USPXXI 1985 in the United States. Despite this, to date, its usage has been far below the required amount. In addition, stability has not been improved yet, and the stable period of inulin preparations manufactured worldwide, including those in the United States, is about one year even after appropriate storage. Since the formulation often turns yellow after passing, the formulation manufactured according to the manufacturing schedule at the manufacturing company cannot be stored sufficiently at the manufacturing company, sales company, or medical institution, and there are restrictions on use. It was the current situation.
Despite the fact that inulin is not recognized as a drug in Japan and inulin preparations are recognized as useful, there are no companies to develop to date and they are mostly used in countries registered as drugs. There is no current situation.
[0003]
[Problems to be solved by the invention]
Accordingly, an object of the present invention is to provide a safe inulin preparation which is excellent in stability and improved in handleability both at the manufacturing site and at the medical site.
[0004]
[Means for Solving the Problems]
In such a situation, the present inventors first added diligent research on insolubility of inulin in order to reduce the burden on medical personnel such as doctors in the medical field, patients, etc., and was excellent in resolubility and stability. Succeeded in producing an inulin-containing preparation and previously filed a patent application (Japanese Patent Application No. 2000-266849).
As a result of further diligent research on the stability of inulin, the present inventors have found that a solution that dissolves or suspends inulin is prone to inulin decomposition at a pH lower than 5.5, and tends to turn yellow at a pH higher than 7. In addition, the present inventors have found that a formulation having further excellent stability can be obtained by the presence of a compound having an inorganic or / and organic buffering action in a liquid preparation containing inulin.
[0006]
The present invention provides inulin selected from hydrochloric acid, phosphoric acid, metaphosphoric acid, citric acid, maleic acid, benzoic acid, carbonic acid, tartaric acid and acetic acid, potassium salts of these acids, sodium salts and amines at room temperature. After adding a solution in which a compound having a buffering action is dissolved and adding an isotonic agent as necessary, the pH is adjusted to 5.5 to 7 and gradually increased to 60 to 110 ° C. over 10 minutes. The present invention provides a method for producing an inulin-containing preparation characterized by dissolving by warming.
[0007]
In the present invention, inulin is selected from hydrochloric acid, phosphoric acid, metaphosphoric acid, citric acid, maleic acid, benzoic acid, carbonic acid, tartaric acid and acetic acid, potassium salts of these acids, sodium salts and amines. Add hot water at 60 to 100 ° C. adjusted to pH 5.5 to 7 by dissolving the compound having a buffering effect, and after adding an isotonic agent as necessary, dissolve to 5 to −40 ° C. The present invention provides a method for producing an inulin-containing preparation characterized by cooling .
[0008]
DETAILED DESCRIPTION OF THE INVENTION
As the inulin used in the present invention, there are very few countries where inulin is currently recognized as a pharmaceutical product, and it is difficult to obtain inulin as a pharmaceutical raw material. be able to. Inulin for food usually has an average molecular weight of 3000 to 7000, and any of these can be used.
Inulin containing no pyrogen is preferred, but when inulin containing pyrogen is used, a solution in which inulin is heated and dissolved is treated with pyrogen-free activated carbon during heating to generate heat. It can also be used after removing the substance.
[0009]
Purified inulin can be collected from the filtrate after, for example, food inulin is dissolved in warm water, treated with activated carbon and a membrane filter when heated and cooled.
Here, the temperature of the hot water only needs to be able to dissolve inulin efficiently, but is preferably in the range of 60 to 90 ° C. Moreover, although the quantity of warm water to be used changes with conditions, such as temperature and the intensity of stirring, about 3 to 10 times by weight of inulin, especially 3 to 5 times by weight is preferable. Further, as the activated carbon, pyrogen-free activated carbon is preferable, and medicinal charcoal listed in Japanese Pharmacopoeia Part 2 can be used. The type of the activated carbon is not particularly limited, but it is preferable to use 1 to 20% by weight of injectable grade activated carbon having exothermic substances and ability to remove coloring substances. Next, inulin having an average molecular weight of about 5000 is usually obtained from the filtrate obtained by filter sterilization with a membrane filter. Further, inulin having an average molecular weight of about 4000 can be obtained by adding acetone to the filtrate and stirring the resulting precipitate by filtration. Acetone is added 5 to 20 times by weight, preferably 5 to 10 times by weight, with respect to the filtrate.
The average molecular weight is a value obtained by comparison with a known standard pullulan using GPC chromatography.
[0010]
As a compound having an inorganic or / and organic buffer action (hereinafter referred to as “compound having a buffer action”), safety has been established, and inulin clearance and measurement of inulin clearance are affected by application to the human body. As long as it can be adjusted to a pH of 5.5 to 7, it can be used as a normal buffer. Specifically, for example, hydrochloric acid, phosphoric acid, inorganic compounds such as meta-phosphoric acid, citric acid, maleic acid, benzoic acid, carbonate acid, tartaric acid, an organic compound such as acetic acid, further 1 salts, such as those mosquitoes potassium, sodium Alternatively, a combination of two or more and various amines can be used.
[0011]
The preparation of the present invention can be produced by, for example, adjusting a pH to 5.5-7, preferably pH 6-7, in the presence of a buffering compound in a solution or suspension containing inulin. . When the pH is less than 5.5, the decomposition of inulin is promoted, and when the pH exceeds 7, the yellowing tends to occur. The pH can be adjusted with an acidic or basic component used as a buffer, sodium hydroxide, or the like.
[0012]
In the pharmaceutical preparation of the present invention, an isotonic agent can be blended as necessary. Examples of the isotonic agent include inorganic salts other than sugars and organic acids, and particularly sodium chloride. preferable. When sodium chloride is used, the concentration is preferably 0 to 5% by weight, and particularly when the preparation is directly applied to the human body, 0.9% by weight close to the osmotic pressure ratio of the body fluid is preferable.
The solution containing inulin is preferably an aqueous solution, particularly an aqueous solution, and physiological saline can also be used.
[0013]
In addition, the preparation of the present invention is prepared by adding a solution in which a compound having a buffering action is dissolved in inulin at room temperature, for example, adding an isotonic agent as necessary, and adjusting the pH to 5.5-7, It can be produced by gradually heating to ˜110 ° C. over 10 minutes and dissolving.
The amount of water used here is preferably 5 to 200 times the weight of inulin. At this time, an isotonic agent can be added as necessary. Moreover, room temperature means the temperature of 1-30 degreeC.
Next, the temperature is gradually raised to 60 to 110 ° C., preferably 70 to 80 ° C. over 10 minutes, preferably over 20 minutes. The rate of temperature rise is not particularly limited as long as it falls within the above range, but it is preferably 1 to 4 ° C./min, particularly 1 to 3 ° C./min. In the present invention, it is preferable to dissolve the inulin by gradually raising the temperature in this way, whereby an inulin-containing preparation excellent in re-solubility can be obtained.
[0014]
After dissolving the inulin by raising the temperature, the solution is preferably cooled to 20 to 70 ° C, particularly 20 to 60 ° C.
The cooled solution is preferably adjusted to a concentration and pH and sterilized as necessary, and then filled into a container, and further cooled to 5 to -40 ° C, particularly -5 to -40 ° C. . The sterilization treatment can be performed by an ordinary method, and for example, it may be filtered through a membrane filter. After sterilization, the solution can be allowed to stand for 1 hour or longer to precipitate inulin to form a suspension, and then filled into a container. Examples of the container include a vial and an ampoule. After filling, the container may be stoppered or melted by a conventional method. The cooling rate is −0.5 to −4 ° C./min, particularly −0.5 to −2 ° C./min, and preferably 0.5 to 1 hour to the target temperature. The temperature after cooling is preferably maintained for about 10 hours, particularly about 1 to 2 hours.
[0015]
Moreover, the formulation of this invention added the hot water of 60-100 degreeC which melt | dissolved the compound which has a buffering effect in inulin, and was adjusted to pH 5.5-7, and the isotonic agent was added as needed. Then, it can manufacture by stirring and dissolving.
It is preferable that hot water is 5-200 weight times with respect to inulin. As the isotonic agent, the same ones as described above can be used in the same manner. Also, the isotonic agent can be dissolved in hot water.
The solution after dissolution is preferably cooled to 5 to -40 ° C, particularly -5 to -40 ° C. The cooling rate is −0.5 to −4 ° C./min, particularly −0.5 to −2 ° C./min, and preferably 0.5 to 1 hour to the target temperature. The temperature after cooling is preferably maintained for about 10 hours, particularly about 1 to 2 hours.
Moreover, after adding hot water to inulin and dissolving, the solution is cooled to 20 to 70 ° C., adjusted for concentration and pH as necessary, sterilized, and filled in a container, and then it is 5 to −40 ° C. It can also be cooled. Sterilization and filling of the container can be performed in the same manner as described above.
[0016]
In any method, the preparation after filling the container can be freeze-dried. Freeze-drying may be performed by a conventional method. For example, after a container filled with a solution containing inulin or the like is cooled to −10 ° C. or lower to freeze the solution, it is gradually reduced under a reduced pressure condition of 0.2 mbar or lower. A lyophilized preparation can be obtained by heating, sublimating the content moisture, and drying. In addition, when the solution after melt | dissolving inulin is cooled to 5--40 degreeC, this can be replaced with lyophilization | freeze-dry, and, thereby, a lyophilized formulation can be obtained.
[0017]
The preparation of the present invention thus obtained is useful as a diagnostic agent used for measuring glomerular filtration rate for grasping renal function. That is, the inulin-containing preparation of the present invention, after being applied to the human body, collects blood and urine at regular intervals, and usually removes free glucose and fructose from these specimens, and then hydrolyzes inulin in the specimens. It can be used as a reagent for calculating the glomerular filtration rate by quantifying the chromogenic product obtained by treating fructose generated by enzymatic degradation with inulinase or β-fructosidase with diphenylamine, resorcin, or anthrone. it can.
[0018]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further, this invention is not limited to these Examples. In addition, Examples 2 to 4 described later are reference examples outside the scope of claims.
[0019]
Reference Example 1 (Production of purified inulin)
To 100 g of inulin for food (average molecular weight 5000; manufactured by Olafty), add 500 mL of hot water at 80 ° C. and stir for 10 minutes. After confirming dissolution, pyrogen-free activated carbon (Shirakaba P, manufactured by Takeda Pharmaceutical Company Limited) 10 g when heated Was added, and the liquid temperature was maintained and stirring was continued for 10 minutes. This solution was sterilized by filtration through a 0.2 to 0.5 μm membrane filter (manufactured by Millipore, USA) when heated, then cooled to 40 ° C., and 10 times by weight of acetone was added to the filtrate and stirred. The resulting precipitate was collected by filtration, air-dried and then dried under reduced pressure at 40 ° C. to obtain 90 g of purified inulin.
The obtained purified inulin had an average molecular weight of about 4000, a white crystalline powder, tasteless and odorless, and was negative in the pyrogen test.
[0020]
Reference Example 2 (Production of purified inulin)
The same operation as in Reference Example 1 was carried out except that acetone was not added, to obtain 85 g of a precipitate. The obtained purified inulin was pyrogen free and had an average molecular weight of about 5000.
[0021]
Reference Example 3 (Production of purified inulin)
Add 100 mL of hot water of 80 ° C. to 100 g of inulin for food (average molecular weight 5000; manufactured by Olafty) and stir for 10 minutes. After confirming dissolution, add 10 g of pyrogen-free activated carbon when heated to maintain the liquid temperature. The stirring was continued for 10 minutes. The solution was filtered through a 0.2 to 0.5 μm membrane filter when heated, and then dried by a spray dryer when heated. The obtained purified inulin was pyrogen free and had an average molecular weight of about 5000.
[0022]
Example 1
To 10 g of purified inulin (average molecular weight 5000), at room temperature, 0.49 g of sodium monohydrogen phosphate dodecahydrate and 0.22 g of potassium dihydrogen phosphate dissolved in 70 mL of water for injection and 0.53 g of sodium chloride were added to pH 6.5. A solution was prepared and dissolved by gradually warming to 80 ° C. in 30 minutes. After confirming dissolution, the solution was cooled to 60 ° C., and water for injection was added to make 100 mL. This was sterilized by filtration through a 0.8 and 0.22 μm membrane filter, and 20 mL thereof was filled into a vial and stoppered to obtain a preparation containing 2 g of inulin.
[0023]
Example 2
To 70 mL of water for injection at 80 ° C., 0.49 g of sodium monohydrogen phosphate 12 hydrate, 0.22 g of potassium dihydrogen phosphate and 0.53 g of sodium chloride are added and dissolved to prepare a pH 6.5 solution. To this solution, 10 g of purified inulin (average molecular weight 5000) was added and dissolved. After confirming dissolution, the solution was cooled to 60 ° C., and water for injection was added to make 100 mL. This was sterilized by filtration through a 0.8 and 0.22 μm membrane filter, and 20 mL thereof was filled into a vial and stoppered to obtain a preparation containing 2 g of inulin.
[0024]
Example 3
To 10 g of purified inulin (average molecular weight 5000), 70 mL of water for injection at 70 ° C. in which 0.49 g of sodium monohydrogen phosphate dodecahydrate and 0.22 g of potassium dihydrogen phosphate are dissolved and 0.53 g of sodium chloride are added and dissolved. After cooling this solution to 40 ° C., it was confirmed that the pH was 6.5, and water for injection was added to make 100 mL. This was sterilized by filtration through a 0.22 μm membrane filter, 20 mL of which was filled into a vial, freeze-dried by a conventional method, rubber stoppered, and aluminum-tightened to obtain a freeze-dried preparation containing 2 g of inulin.
[0025]
Example 4
To 70 mL of water for injection at 80 ° C., 0.21 g of citric acid and 0.73 g of sodium chloride were added and dissolved, and 0.1 mol / L sodium hydroxide solution was added to adjust the pH to 6.5. To this solution, 10 g of purified inulin (average molecular weight 5000) was added and dissolved. After confirming dissolution, the solution was cooled to 60 ° C. and water for injection was added to make 100 mL. This was sterilized by filtration through a 0.8 and 0.22 μm membrane filter, and 20 mL thereof was filled into a vial and stoppered to obtain a preparation containing 2 g of inulin.
[0026]
Example 5
90 g of 80 ° C. water for injection dissolved in 0.21 g of citric acid was added to 10 g of purified inulin and dissolved, then 0.73 g of sodium chloride was added, and then the solution was cooled to 60 ° C., and 0.01 mol / L water The pH was adjusted to 6.5 with an aqueous sodium oxide solution, and water for injection was added to make 100 mL. This was sterilized by filtration through a 0.22 μm membrane filter, 20 mL of which was filled into a vial, and the vial was sealed with a rubber stopper and aluminum fastening.
The vial was immediately cooled to −10 ° C. by a freezer at a rate of −10 ° C./10 minutes, held at this temperature for 1 hour, and then warmed to 20 ° C. at a rate of 10 ° C./10 minutes. A formulation containing 2 g was obtained.
[0027]
Comparative Example 1
To 10 g of purified inulin (average molecular weight 5000), 70 mL of water for injection and 0.9 g of sodium chloride were added at room temperature to adjust to pH 6.5, and the mixture was heated to 80 ° C. to dissolve. After confirming dissolution, the solution was cooled and water for injection was added to make 100 mL. This was sterilized by filtration through a 0.8 and 0.22 μm membrane filter, and 20 mL thereof was filled into a vial and stoppered to obtain a preparation containing 2 g of inulin.
[0028]
Test example 1
The preparations obtained in Example 1 and Comparative Example 1 were subjected to a stability test.
That is, the appearance, pH, and reducing sugar content when each preparation was stored at 40 ° C., 50 ° C. and 60 ° C. were evaluated. The results are shown in Tables 1-6.
[0029]
[Table 1]

[0030]
[Table 2]

[0031]
[Table 3]

[0032]
[Table 4]

[0033]
[Table 5]

[0034]
[Table 6]

[0035]
【The invention's effect】
The inulin-containing preparation of the present invention is one in which the stability of inulin is remarkably improved without inulin being decomposed or yellowing of the preparation. It is useful for measuring glomerular filtration rate used for grasping renal function.

Claims (4)

Inulin has a buffering action selected from hydrochloric acid, phosphoric acid, metaphosphoric acid, citric acid, maleic acid, benzoic acid, carbonic acid, tartaric acid and acetic acid, potassium salts of these acids, sodium salts and amines at room temperature. After adding a solution in which the compound is dissolved and adding an isotonic agent as necessary, the pH is adjusted to 5.5 to 7, and gradually heated to 60 to 110 ° C. over 10 minutes to dissolve. A method for producing an inulin-containing preparation. After dissolving the inulin was heated process according to claim 1, wherein the solution is cooled to 20 to 70 ° C.. A compound having a buffering action selected from hydrochloric acid, phosphoric acid, metaphosphoric acid, citric acid, maleic acid, benzoic acid, carbonic acid, tartaric acid and acetic acid, potassium salts of these acids, sodium salts and amines. It is characterized by adding hot water at 60 to 110 ° C. adjusted to pH 5.5 to 7 and adding an isotonic agent as necessary, and then dissolving and cooling to 5 to −40 ° C. A method for producing an inulin-containing preparation. An inulin-containing preparation obtained by the method according to any one of claims 1 to 3 .