JP3136306B2 - Sodium nitroprusside injection for intravenous injection - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to improving the stability of an aqueous solution of sodium nitroprusside (hereinafter abbreviated as "NP sodium") to 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 decrease in residual rate due to exposure.

[0002]

2. Description of the Related Art Sodium NP has long been used as a reagent for the reaction of aldehydes, ketones, steroids and SH compounds, but since it was discovered by Johnsonn in 1929 that it had a strong blood pressure lowering effect, It is used for the treatment of malignant hypertension and myocardial infarction attacks, 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 hospitals using a reagent, and its usefulness has been reported. However, NP sodium aqueous solution is extremely unstable to light, In this case, it is necessary to shield light with aluminum foil or the like. The necessity of such light shielding is not only inconvenient in handling, but also causes a problem that exposure due to incomplete light shielding or falling off of the light shielding member may cause intravenous infusion of a drug containing a decomposition product.

[0004] When an NP sodium aqueous solution is used for intravenous drip or the like, it is necessary to sterilize by heating or to prepare a sterile preparation by a sterile filtration method in advance. In general, heat sterilization is excellent in terms of simplicity of operation, ease of condition control, and reliability of sterilization. However, an NP sodium aqueous solution is an intravenous preparation that is turbid or precipitates when heat sterilized. Has very disadvantageous disadvantages and is not suitable for heat sterilization.

[0005] These instabilities to heat and light are caused by NP
This was an obstacle to the wide use of sodium by injection, intravenous drip, etc.

The present inventors conducted tests using various lots of NP sodium having a purity of 99.0% or more and showing no impurities by thin-layer chromatography, and found that all of them produced turbidity or precipitate. From these facts, it was concluded that these turbidities or precipitates were not caused by potential impurities in NP sodium used as a raw material, but were caused by partial decomposition of NP sodium by heating.

[0007]

Means for Solving the Problems The present inventors firstly provide:
Various substances were examined in detail in search of a stabilizer for preventing turbidity and precipitation from occurring due to heating of the NP sodium aqueous solution. As a result, by adding 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, to the NP sodium-containing aqueous solution, Turbidity and precipitation can be prevented. The ratio of these heat stabilizers to NP sodium is 0.0
It was also found that 1 mmol / 30 mg (stabilizer / sodium NP) 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 the pH adjustment, the pH of the aqueous solution is preferably adjusted to 6 or less, particularly preferably p
H4 to H6. In the adjustment, for example, citric acid is preferably used.

The addition of these heat stabilizers makes it possible to perform heat sterilization without causing turbidity or sedimentation, so that the production of a sterilized aqueous solution of sodium NP becomes extremely easy. This allows for widespread use of NP sodium in medical settings.

On the other hand, as described above, the NP sodium aqueous solution is extremely unstable to light. Even when the above stabilizer against heat is used, stabilization with respect to light cannot be expected, so that it is necessary to shield light when using. Thus, the problem of inconvenience of use still exists. Therefore, in order to solve this inconvenience and further increase the utility of NP sodium, a detailed study was conducted in search of 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 the aqueous NP sodium solution. The ratio of the stabilizer to light to sodium NP is 0.002 mmol / 3.
It has also been found that 0 mg (stabilizer / sodium NP) is preferable. Therefore, by adding such a stabilizer against light, it is possible to provide a preparation which does not require the conventional light-shielding.

The above-mentioned heat or light stabilizers can be used alone. For example, if a simple and reliable light-shielding method can be used, the use of an NP sodium aqueous solution can be facilitated by using only a heat stabilizer, and a well-controlled filtration sterilization is carried out on a daily basis. If only a light stabilizer is used, the NP
Use of an aqueous sodium solution can be facilitated. On the other hand, these stabilizers against heat or light can be used in combination of both, whereby both stabilizing effects can be exerted at the same time. That is, when both stabilizers are added together, heat sterilization can be performed without causing turbidity or precipitation, and the necessity of shading during use is eliminated. It becomes even easier.

[0013]

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

[Example 2] 0.3 g of sodium NP and 0.2 g (1.09 mmol) of sorbitol were added to distilled water for injection to make the total amount 100 mL, followed by filtration through a membrane filter, and 2 mL of the filtrate to a volume of 2 mL. Fill into an ampoule and heat sterilize.

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 and dissolved to give a total amount. After adjusting to 100 mL, the solution is filtered through a membrane filter, and 2 mL of the filtrate is filled into a 2 mL ampoule and sterilized by heating.

Example 4 0.3 g of sodium NP, 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 make a total volume of 100 mL. After that, the solution is filtered through a membrane filter, and 2 mL of the filtrate is filled into an ampoule having a capacity of 2 mL and sterilized by heating.

Test Example 1 According to the procedures described in Examples 1 to 4, each of the stabilizers of citric acid, sodium citrate, sorbitol, tartaric acid and phosphate was sterilized by heating at 100 ° C. for 1 hour. The presence or absence of later turbidity and precipitation was visually confirmed. As a control solution, distilled water for injection was added to 0.3 g of sodium nitroprusside to dissolve the same, and the same operation was performed except that the total amount was 100 mL. Table 1 shows the results.

[0018]

[Table 1]

As shown in the table, the control solution caused precipitation, but no turbidity or precipitation was observed in any of the solutions to which the stabilizer was added.

Test Example 2 The effect of pH on turbidity and precipitation of an aqueous solution of sodium nitroprusside was examined. After adjusting the NP sodium concentration to 0.3 w / v%, pH 1.1 with hydrochloric acid, pH 4 to 8 with citric acid and sodium hydrogen phosphate, and heat sterilizing at 100 ° C. for 1 hour, spot 10 μL of this solution on a TLC plate. And expand,
A search was made for the presence or absence of decomposition 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, and 1.1 g of citric acid to make 100 mL by adding water / isopropyl alcohol (45/55). Coloring reagent: 1 g of ferrous sulfate is added with 2N aqueous sulfuric acid
A solution that was dissolved to 100 mL. Table 2 shows the results.

[0021]

[Table 2]

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

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

[0024]

[Table 3]

The residual ratio of NP sodium 5 days after the start of the test was 59.2% when CS sodium was not added, but was 72.6% and 0.05 when 0.01 w / v% was added.
With the addition of w / v%, 88.1% and with the addition of 0.25 w / v%, 95.3%, the stability of NP sodium was improved as the amount of CS sodium increased.

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

[0027]

[Table 4]

The residual ratio of NP sodium 5 days after the start of the test was 60.3% in the case where disodium FAD was not added, but was 64.0% and 0.0% in the case where 0.002 w / v% was added.
The NP sodium stability was improved as the addition amount of disodium FAD increased to 81.8% with the addition of 2 w / v% and 93.8% with the addition of 0.2 w / v%.

[Test Example 5] NP sodium 0.3 w / v
%, CS sodium 0.05% w / v% or FAD disodium 0.1% w / v%, pH adjusted to 5 with sodium hydrogen phosphate and citric acid, diluted 50-fold with 5% dextrose for injection. 500 ml of this solution is placed in a colorless vial (solution A or solution B, respectively) and
After adjusting to 0 lux and exposing for 16 hours, the content of NP sodium was measured. As a control solution, a 0.3% aqueous solution of NP sodium was similarly diluted with a 5% glucose solution for injection (solution C). Table 5 shows the results.

[0030]

[Table 5]

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

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-58-129260 (JP, A) JP-A-1-224667 (JP, A) JP-B-1-24133 (JP, B2) (58) Field (Int.Cl. ⁷ , DB name) A61K 9/00-9/72 A61K 47/00-47/48 C01G 49/00-49/16

Claims (4)

(57) [Claims] (1) an aqueous solution containing sodium nitroprusside as a principal agent, and at least one compound selected from the group consisting of citric acid, sodium citrate, tartaric acid, sodium hydrogen phosphate and sorbitol as a stabilizer; A stable sodium nitroprusside injection for intravenous injection, comprising a sterile aqueous solution containing sodium carbazochromesulfonate. 2. The ratio of a compound selected from the group consisting of citric acid, sodium citrate, tartaric acid, sodium hydrogen phosphate and sorbitol to sodium nitroprusside is 0.1% per 30 mg of sodium nitroprusside.
The injection according to claim 1, wherein the amount is at least 01 mmol. 3. The injection according to claim 1, wherein the ratio of sodium carbazochromesulfonate to sodium nitroprusside is 0.002 mmol or more per 30 mg of sodium nitroprusside. 4. The injection according to claim 1, wherein the pH is adjusted to 4 to 6.