JPH07126017A - Precipitation prevention and stabilization of aqueous sodium nitroprusside - Google Patents

Abstract

PURPOSE:To prevent aqueous sodium nitroprusside from causing turbidity and precipitation and/or improve the stability to light. CONSTITUTION:At least one selected from the group of citric acid, tartaric acid, malic acid and their sodium salts and sorbitol and/or at least one selected from the group of sodium carbazochrome sodium sulfonate and flavin adenine dinucleotide disodium are added to the aqueous solution of sodium nitroprusside as stabilizer whereby the solution is prevented from formation of turbidity and precipitation and/or improve the stability to light.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to improvement of the stability of an aqueous solution of sodium nitroprusside (hereinafter abbreviated as "NP sodium") against heat and / or light. More specifically, the present invention relates to prevention of turbidity or precipitation due to heating of an NP sodium aqueous solution, and / or prevention of reduction in residual rate due to exposure.

[0002]

BACKGROUND OF THE INVENTION Sodium NP has been used as a reaction reagent for aldehydes, ketones, steroids and SH compounds for a long time. It has been used for treatment of malignant hypertension and myocardial infarction attack, and is currently sold as an injectable powder outside Japan.

On the other hand, in Japan, NP sodium is used as a pharmaceutical preparation in a hospital by using a reagent, and its usefulness has been reported. However, the NP sodium aqueous solution is extremely unstable to light and is administered by intravenous drip infusion. In that case, it is necessary to shield from light with aluminum foil or the like. The necessity of such light shielding is not only inconvenient to handle, but also there is a problem in that the drug containing the decomposed product can be intravenously infused intravenously by exposure due to incomplete light shielding or dropping of the light shielding member.

When an aqueous solution of sodium NP is used for intravenous drip infusion or the like, it is necessary to sterilize it in advance by heating or to prepare a sterile preparation by a sterile filtration method. Heat sterilization is generally superior in terms of ease of operation, ease of condition management, and certainty of sterilization. However, an aqueous solution of sodium NP is used as an intravenous preparation because it causes turbidity or precipitation when heat sterilized. Has very disadvantageous drawbacks and is not suitable for heat sterilization.

These heat and light instabilities cause NP
It was an obstacle to the widespread use of sodium by injection and intravenous drip.

The inventors of the present invention tested various lots of NP sodium having a purity of 99.0% or more and showing no impurities by thin layer chromatography, and found that turbidity or precipitation occurred. Therefore, it was concluded that these turbidity or precipitation was not due to latent impurities in NP sodium used as a raw material but due to partial decomposition of NP sodium due to heating.

[0007]

The present inventors first of all,
Various substances were studied in detail for a stabilizer for preventing the occurrence of turbidity and precipitation due to heating of the NP sodium aqueous solution. As a result, at least one compound selected from the group consisting of citric acid, tartaric acid and phosphoric acid and their sodium salts and sorbitol, particularly preferably citric acid or its sodium salt, is added to the NP sodium-containing aqueous solution. It was found that turbidity and precipitation can be prevented. The ratio of these heat stabilizers to sodium NP is 0.0
It was also found that 1 mmol / 30 mg (stabilizer / NP sodium) or more is preferable.

It has also been found that the aqueous NP sodium solution has better thermal stability on the acidic side than on the alkaline side. That is, in adjusting the pH, the pH of the aqueous solution is preferably 6 or less, and particularly preferably p
H4 to 6 For the adjustment, it is preferable to use citric acid, for example.

The addition of these heat stabilizers enables heat sterilization without causing turbidity or precipitation, so that the production of a sterile aqueous solution of sodium NP becomes extremely easy. This allows the widespread use of sodium NP in the medical setting.

On the other hand, as described above, the NP sodium aqueous solution is extremely unstable with respect to light. Even when the above-mentioned stabilizer against heat is used, stabilization against light cannot be expected, and therefore it is necessary to shield the light before use. Therefore, the problem of being inconvenient to use still exists. Therefore, in order to eliminate this inconvenience and further enhance the availability of NP sodium, a detailed study was conducted in search of a means for stabilizing against light.

As a result, sodium carbazochrome sulfonate (hereinafter abbreviated as "CS sodium") and flavin adenine dinucleotide disodium (hereinafter "F").
AD disodium ". ), Alone or in combination, improve the photostability of aqueous NP sodium solution. The ratio of these stabilizers to light to sodium NP is 0.002 mmol / 3.
It has also been found that 0 mg (stabilizer / sodium NP) or higher is preferred. Therefore, by adding these stabilizers against light, it is possible to provide a preparation which does not require the conventional light shielding.

Only one of the above-mentioned heat or light stabilizers can be used. For example, when a simple and reliable light-shielding method can be used, it is possible to facilitate the use of the NP sodium aqueous solution by using only a stabilizer against heat, and a well-controlled filter sterilization is routinely used. NP by using only light stabilizers if already performed as
The use of aqueous sodium solution can be facilitated. On the other hand, these heat or light stabilizers can be used in combination with each other, whereby the stabilizing effects of both can be exhibited at the same time. That is, when both stabilizers are added together, it is possible to heat sterilize without causing turbidity or precipitation and to eliminate the need for light shielding during use, and thus it is possible to use an aqueous solution of NP sodium for intravenous drip infusion and the like. It will be easier.

[0013]

The present invention will be more specifically illustrated and described below with reference to particularly preferred examples. [Example 1] 0.3 g of NP sodium and 0.6 g (2.32 mmol) of sodium citrate were added to distilled water for injection to make the total amount 100 mL, and the mixture was filtered through a membrane filter, and 2 mL of the filtrate was taken in an ampoule having a volume of 2 mL. And heat sterilize.

[Example 2] 0.3 g of NP sodium and 0.2 g (1.09 mmol) of sorbitol were added to distilled water for injection to dissolve it, and the total amount was 100 mL, followed by filtration with a membrane filter, and 2 mL of the filtrate having a volume of 2 mL. Fill the ampoule with and sterilize by heating.

[Example 3] 0.3 g of sodium NP, 0.005 g (0.033 mmol) of tartaric acid, and 0.01 g (0.07 mmol) of sodium hydrogen phosphate (anhydrous) were added to distilled water for injection to dissolve the whole amount. After making 100 mL, it is filtered with a membrane filter, and 2 mL of the filtrate is filled in an ampoule having a volume of 2 mL and sterilized by heating.

[Example 4] 0.3 g of NP sodium, 0.01 g (0.070 mmol) of sodium hydrogen phosphate and 0.006 g (0.031 mmol) of citric acid were added to distilled water for injection and dissolved to bring the total volume to 100 mL. After that, it is filtered through a membrane filter, and 2 mL of the filtrate is filled in an ampoule having a volume of 2 mL and sterilized by heating.

[Test Example 1] By the procedure described in Examples 1 to 4, heat sterilization was performed at 100 ° C. for 1 hour using each stabilizer of citric acid, sodium citrate, sorbitol, tartaric acid, and phosphate. The presence or absence of turbidity and precipitation afterward was visually confirmed. Distilled water for injection was added and dissolved in 0.3 g of sodium nitroprusside as a control solution, and the total amount was 100 mL, and the same operation was performed. The results are shown in Table 1.

[0018]

[Table 1]

As shown in the table, precipitation occurred in the control solution, but neither turbidity nor precipitation was observed in any of the solutions to which the stabilizer was added.

[Test Example 2] The influence of pH on the occurrence of turbidity and precipitation of an aqueous sodium nitroprusside solution was examined. NP sodium concentration was 0.3 w / v%, pH was 1.1 with hydrochloric acid, pH 4 to 8 with citric acid and sodium hydrogen phosphate, and after heat sterilization at 100 ° C. for 1 hour, 10 μL of this solution was spotted on a TLC plate. Then expand,
We searched for the presence or absence of degradation products. The operating conditions for thin layer chromatography are as follows. TLC plate: Pre-Coat TLC Plate Cellulose (Merck,
Thickness 0.1 mm) Developing solvent: 5 g of sodium nitrate, 1.4 g of disodium phosphate, 1.1 g of citric acid to which water was added to make 100 mL / isopropyl alcohol (45/55). Coloring reagent: 1N ferrous sulfate was added with 2N sulfuric acid aqueous solution,
A solution that was dissolved to make 100 mL. Table 2 shows the results.

[0021]

[Table 2]

At pH 1 to 6.2, no spots other than sodium NP were observed. pH 7.1 and 8.0
Then, spots of ferrocyan ion were recognized in addition to spots of NP sodium. Therefore, the NP sodium aqueous solution is more stable at a pH of about 6 or less as compared with the alkaline side.

[Test Example 3] NP sodium concentration was 0.3
w / v%, pH is adjusted to 5 with citric acid and sodium hydrogen phosphate, and sodium CS is 0.01 as a light stabilizer.
(0.003 mmol / 10 mL) to 0.25 w / v%
Prepare to a concentration of (0.007 mmol / 10 mL) and fill a colorless ampoule with a volume of 10 mL with 10 mL,
After adjusting to 1000 lux with a fluorescent lamp, the residual rate of NP sodium was examined using high performance liquid chromatography. The conditions of high performance liquid chromatography are as follows. Equipment: M-600E system (Waters) Column: Stainless steel inert silt ODS 4.6 mm
(Inner diameter) × 150 mm (GL Sciences) Column temperature: Constant temperature around 30 ° C Flow rate: 1 mL / min Detector: UV spectrophotometer (250 nm) Mobile phase: 550 mL of water, 4.8 g of dipotassium hydrogen phosphate
And tetra-n-butylammonium hydrogen sulfate 4.7 g
Was added, stirred and dissolved, 450 mL of acetonitrile was added, and the pH was adjusted to 6 with phosphoric acid. The results are shown in Table 3.

[0024]

[Table 3]

The residual rate of NP sodium 5 days after the start of the test was 59.2% when CS sodium was not added, but 72.6% and 0.05 when 0.01 w / v% was added.
The stability of NP sodium was improved according to the increase in the amount of sodium CS, which was 88.1% with the addition of w / v% and 95.3% with the addition of 0.25 w / v%.

Test Example 4 Instead of the sodium CS used in Test Example 3, 0.002 of FAD disodium was used.
(0.00024mmol / 10mL) to 0.2w / v%
(0.024mmol / 10mL), and add NP
The stability of sodium was investigated. The test conditions and analysis conditions are the same as in Test Example 3. The results are shown in Table 4.

[0027]

[Table 4]

The residual rate of NP sodium after 5 days from the start of the test was 60.3% when FAD disodium was not added, but it was 64.0% and 0.0 when 0.002 w / v% was added.
The NP sodium stability was improved according to the increase in the amount of FAD disodium added, which was 81.8% with the addition of 2 w / v% and 93.8% with the addition of 0.2 w / v%.

[Test Example 5] Sodium NP 0.3 w / v
%, Sodium CS 0.05 w / v% or disodium FAD 0.1 w / v%, and a solution having a pH of 5 with sodium hydrogen phosphate and citric acid was diluted 50 times with 5% glucose solution for injection. , 500mL of this solution was put into a colorless vial (A solution or B solution, respectively), and 200 with a fluorescent lamp.
The content of sodium NP was measured after adjusting for 0 lux and exposing for 16 hours. As a control solution, 0.3 w / v% sodium NP solution was similarly diluted with 5% glucose solution for injection (solution C). Table 5 shows the results.

[0030]

[Table 5]

The residual ratio of NP sodium in the sample A solution containing CS sodium added after 6 hours was 97.4% and 90.7% even after 16 hours. The residual rate was 96.8% after 6 hours and 89.9% after 16 hours as in the case of the solution A. It was 89.3% and 73.6% in the control solution C.
Is a solution or FAD obtained by adding 5 mg (about 0.016 mmol) of sodium CS to 30 mg of NP sodium.
The solution containing 10 mg (about 0.012 mmol) of disodium significantly improved the stability of NP sodium against light.

Claims (12)

[Claims] 1. A method for preventing the occurrence of turbidity and precipitation of an aqueous sodium nitroprusside solution, which is selected from the group consisting of citric acid, tartaric acid and phosphoric acid, and their sodium salts and sorbitol as stabilizers. At least one compound contained therein. 2. The ratio of the stabilizer to sodium nitroprusside is 0.01 mmol / 30 mg (stabilizer / sodium nitroprusside) or more,
The method of claim 1. 3. An aqueous solution containing sodium nitroprusside, which further comprises, as a stabilizer, at least one compound selected from the group consisting of citric acid, tartaric acid and phosphoric acid, their sodium salts, and sorbitol. Aqueous solution. 4. The ratio of the stabilizer to sodium nitroprusside is 0.01 mmol / 30 mg (stabilizer / sodium nitroprusside) or more,
The aqueous solution according to claim 3. 5. A method for stabilizing an aqueous sodium nitroprusside solution against light, characterized in that the aqueous sodium nitroprusside solution contains sodium carbazochrome sulfonate and / or flavin adenine dinucleotide disodium as a stabilizer. And how to. 6. The method according to claim 5, wherein the ratio of the stabilizer to sodium nitroprusside is 0.002 mmol / 30 mg (stabilizer / sodium nitroprusside) or more. 7. An aqueous solution containing sodium nitroprusside, which contains sodium carbazochrome sulfonate and / or disodium flavin adenine dinucleotide as a stabilizer. 8. The aqueous solution according to claim 7, wherein the ratio of the stabilizer to sodium nitroprusside is 0.002 mmol / 30 mg (stabilizer / sodium nitroprusside) or more. 9. A method for preventing turbidity and precipitation of an aqueous sodium nitroprusside solution and stabilizing it against light, wherein the aqueous sodium nitroprusside solution is used as a stabilizer with citric acid, tartaric acid and phosphoric acid. A method comprising incorporating at least one compound selected from the group consisting of these sodium salts and sorbitol, and at least one compound selected from the group consisting of sodium carbazochrome sulfonate and flavin adenine dinucleotide disodium. 10. An aqueous solution containing sodium nitroprusside, which comprises, as a stabilizer, at least one compound selected from the group consisting of citric acid, tartaric acid and phosphoric acid, their sodium salts and sorbitol, and sodium carbazochrome sulfonate. And an at least one compound selected from the group consisting of flavin adenine dinucleotide disodium. 11. A method according to claim 1, 2, 5, 6 or 9, wherein the pH of the aqueous solution is 4 to 6. 12. The aqueous solution according to claim 3, 4, 7, 8 or 10, wherein the pH of the aqueous solution is 4 to 6.