JP2000072673A - Nicardipine hydrochloride-containing liquid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject liquid preparation having high stability and safety and capable of keeping a prescribed concentration over a long period by dissolving nicardipine hydrochloride into a buffer solution in a specific molar concentration range and keeping oxygen in a vessel in a constant concentration or below. SOLUTION: This liquid preparation is obtained by dissolving nicardipine hydrochloride in a buffer solution (preferably a tartaric acid buffer solution, a citric acid buffer solution, or the like) in a concentration of 0.0001-0.1 mol/l, preferably 0.0005-0.01 mol/l. In the liquid preparation, the pH is 3.0 4.5, preferably 3.0-4.0 and the concentration of oxygen dissolved therein after treatment at 100 deg.C for 168 hr is <=3 mg/l, preferably <=2.5 mg/l. The liquid preparation is preferably packed in an ampule, and an ampule having light-shielding property is especially preferably used as the ampule.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a liquid preparation containing nicardipine hydrochloride which has high safety and excellent stability. More specifically, the present invention relates to a liquid preparation containing nicardipine hydrochloride, which is prepared using an acidic buffer solution and is stabilized by reducing the amount of oxygen in a container to a certain amount or less.

[0002]

2. Description of the Related Art Nicardipine hydrochloride has effects such as cerebral vasodilation, coronary vasodilation, and blood pressure lowering by calcium antagonism. Tablets and powders were used in 1981, and its amorphous substance was used in 1988. Has been released and is the drug of choice in the clinic for various indications. In 1989, injections were released for emergency treatment of abnormal hypertension such as surgery and hypertensive emergency.

In the preparation of an injection of nicardipine hydrochloride, a polyhydric alcohol such as sorbitol, mannitol, xylitol, propylene glycol or the like is contained in an amount of 2 to 7% w / v for the purpose of stabilization, dissolution aid and isotonicity. (Japanese Patent Publication No. 2-47964), and in actual preparations, D-sorbitol 50 times the amount of nicardipine hydrochloride (5 w / v% as an injection) is added. This is because nicardipine hydrochloride is hardly soluble in water, and even if a chemical solution is prepared by adding a polyhydric alcohol, the pH range showing good solubility is narrow, and the stability is increased by the elution of alkali components from the ampoule. When sodium chloride, which is usually used as a tonicity agent, is added, the solubility of nicardipine hydrochloride in the drug solution is reduced, and an injection having a predetermined concentration cannot be obtained, or nicardipine hydrochloride precipitates. The reason for this is that ordinary tonicity agents cannot be used.

[0004]

However, D-sorbitol has to be carefully administered to patients with diabetes insipidus and patients with impaired liver and kidney, and rapid and large-volume injections are required. Is a compound that may cause electrolyte loss. Furthermore, D-sorbitol has a dehydration effect on the intestinal tract wall and other tissues and edema tissue due to its osmotic dehydration effect, and is contraindicated in patients with hypotonic dehydration and hereditary fructose intolerance. Limited. Moreover, these have only been found to be sorbitol-related effects, and the details of their mechanism of action are unclear. Attention is needed. In particular, nicardipine hydrochloride injection is used in emergencies in the medical field due to the usage characteristics of its indications, so it is assumed that it may be administered without discovering these diseases, and special attention should be paid to its safety. It is an appropriate drug.

[0005] Conventional nicardipine hydrochloride injections using a large amount of D-sorbitol as described above are
There were many issues that needed to be improved in terms of safety and usefulness in handling. Therefore, an object of the present invention is to provide a nicardipine hydrochloride-containing liquid preparation which has higher stability without using D-sorbitol, is highly safe, and can maintain a predetermined concentration for a long period of time.

[0006]

Under these circumstances, the present inventors have conducted intensive studies and, as a result, have dissolved isotonic acid buffer by dissolving nicardipine hydrochloride in an acidic buffer to make the oxygen in the container less than a certain concentration to make it isotonic. Even in the liquid preparations, without using D-sorbitol, which was conventionally essential, the crystallization of the active ingredient, the formation of decomposed products is suppressed, and a very stable nicardipine hydrochloride solution or an isotonic injection solution maintaining the pH is obtained. Can be manufactured, and furthermore, the range of formulation conditions of the preparation of the present invention is
The present invention was completed by confirming the specific residual amount of nicardipine hydrochloride after 168 hours at 100 ° C., precipitation of crystals in the solution, change in pH, and the like.

That is, according to the present invention, nicardipine hydrochloride is used in an amount of 0.1%.
0001-0.1 mol / l dissolved in buffer, pH 3.0
The present invention relates to a liquid preparation containing nicardipine hydrochloride, characterized in that the dissolved oxygen in the drug solution after treatment at 100 ° C for 168 hours is 3 mg / l or less.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Preferred buffers used in the present invention include tartrate buffer and citrate buffer.

The concentration of the buffer must be from 0.0001 to 0.1 mol / l, preferably from 0.0005 to 0.01 mol / l. Concentration 0.0
If it is less than 001 mol / l or exceeds 0.1 mol / l, the stability of nicardipine hydrochloride tends to be impaired.

[0010] The pH of the drug solution must be in the range of 3.0 to 4.5, and the pH must be maintained over the effective period of the drug. For this purpose, it is preferable to adjust the pH at the time of preparing the drug solution to a range of 3.0 to 4.0.

The amount of oxygen in the container of the liquid preparation containing nicardipine hydrochloride of the present invention (ie, the sum of the amount of dissolved oxygen in the drug solution and the amount of oxygen in the space in the container (when there is space in the container such as an ampule)) is The dissolved concentration in the drug solution after treatment at 100 ° C. for 168 hours needs to be 3 mg / l or less, but is preferably 2.5 mg / l or less. If the amount of oxygen in the container exceeds 3 mg / l as the dissolved concentration in the drug solution after the above treatment, the stability of nicardipine hydrochloride is impaired, the residual rate during long-term storage is reduced, and the expected nicardipine hydrochloride is reduced. The concentration cannot be maintained.

In order to maintain the dissolved oxygen concentration of 3 mg / l or less as a drug solution after treatment at 100 ° C. for 168 hours, it is necessary to use a solution containing dissolved oxygen in the drug solution and an ampoule having a space in the preparation. It is preferable to reduce or eliminate oxygen in this space, and the removal of spatial oxygen is particularly effective. Examples of a method for reducing or removing dissolved oxygen in a chemical solution include a method in which nitrogen gas is blown into the chemical solution to drive out dissolved oxygen, and a method in which oxygen is directly removed using sodium pyrosulfate, sodium bisulfite, or the like. Examples of the method for reducing or removing oxygen in the space include a method in which the above-described step of removing dissolved oxygen is performed in a nitrogen atmosphere, a method in which nitrogen is substituted in the container during sealing, and the like. The dissolved oxygen concentration during preparation is preferably 8 mg / l or less, particularly 6 mg / l or less, and the spatial oxygen concentration is preferably 2 v / v% or less. However, in the step of reducing the dissolved oxygen and the oxygen in the space in these chemicals, the formulation is carried out in a strictly low-oxygen-concentration purified water using a low-oxygen-concentration or oxygen-free gas atmosphere. As long as the dissolved oxygen concentration of the drug solution after the treatment can be kept at 3 mg / l or less, there is no need to incorporate it as a special step.

When the liquid preparation containing nicardipine hydrochloride of the present invention is prepared as an injection, a commonly used tonicity agent such as sodium chloride can be blended. Unlike conventional products, the solubility of nicardipine hydrochloride is also different in this case. Does not occur.

The liquid preparation containing nicardipine hydrochloride of the present invention is preferably filled in an ampoule, and in particular, a light-shielding ampoule is preferably used.

The nicardipine hydrochloride-containing liquid preparation of the present invention is prepared by, for example, preparing a 0.0001 to 0.1 mol / l acidic buffer having a pH of 3.0 to 4.0 using purified water, and dissolving a predetermined amount of nicardipine hydrochloride by the buffer. The process can be carried out by arbitrarily combining the step of reducing the amount of dissolved oxygen in the solution and the step of reducing the amount of spatial oxygen in the container.

[0016]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

The amount of dissolved oxygen in the chemicals in the following Examples and Controls was 20 ° C. before the treatment at 100 ° C. for 168 hours, and after cooling at room temperature after the treatment. At a temperature of 25 ° C, a dissolved oxygen meter (DO meter manufactured by Iijima Electronics Co., Ltd.)
B-505).

Example 1 To about 700 ml of water for injection, 0.15 g of tartaric acid was added and dissolved while stirring, and about 30 ml of a 0.02 mol / l aqueous sodium hydroxide solution was further added.
Was added. 1g of nicardipine hydrochloride with stirring
And dissolved. After confirming dissolution, sodium chloride 8.9 g
After adding water for injection, add 1000
ml, and it was confirmed that the pH of the drug solution was about 3.5 and the dissolved oxygen was 8.0 mg / l. Then, the mixture was filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less. Later, it was closed. Then at 121 ° C for 20
The solution was sterilized for a minute and used as an injection. Dissolved oxygen amount in chemical solution: 8.0 mg / l Oxygen amount in space: 2 v / v% or less pH of chemical solution: 3.5 Buffer solution: 0.001 mol / l tartrate buffer

Example 2 To about 700 ml of water for injection, 0.15 g of tartaric acid was added and dissolved while stirring, and about 30 ml of 0.02 mol / l aqueous sodium hydroxide solution was further added.
Was added. 1g of nicardipine hydrochloride with stirring
And dissolved. After confirming dissolution, sodium chloride 8.9 g
After adding water for injection, add 1000
ml, and the pH of the solution was confirmed to be about 3.5.
Next, oxygen dissolved in the solution was replaced with nitrogen, and the dissolved oxygen in the drug solution was adjusted to about 6.0 mg / l, and then filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less. Later, it was closed. Then 121 ° C
For 20 minutes to give an injection. Dissolved oxygen in drug solution: 6.0mg / l Oxygen amount in space: 2v / v% or less pH of drug solution: 3.5 Buffer: 0.001mol / l tartrate buffer

Example 3 Tartaric acid (0.15 g) was added to about 700 ml of water for injection while stirring to dissolve the mixture, and a 0.02 mol / l aqueous sodium hydroxide solution of about 30 ml was further added.
Was added. 1g of nicardipine hydrochloride with stirring
And dissolved. After confirming dissolution, sodium chloride 8.9 g
After adding water for injection, add 1000
ml, and the pH of the solution was confirmed to be about 3.5.
Next, oxygen dissolved in the solution was replaced with nitrogen, and the dissolved oxygen in the drug solution was reduced to about 4.0 mg / l, and then filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less. Later, it was closed. Then 121 ° C
For 20 minutes to give an injection. Dissolved oxygen in drug solution: 4.0mg / l Oxygen in space: 2v / v% or less pH of drug solution: 3.5 Buffer: 0.001mol / l tartrate buffer

COMPARATIVE EXAMPLE 1 Tartaric acid (0.15 g) was added to about 700 ml of water for injection while stirring to dissolve the mixture, and a 0.02 mol / l aqueous sodium hydroxide solution of about 30 ml was further added.
Was added. 1g of nicardipine hydrochloride with stirring
And dissolved. After confirming dissolution, sodium chloride 8.9 g
After adding water for injection, add 1000
ml, and the pH of the solution was confirmed to be about 3.5.
Next, oxygen dissolved in the solution was replaced with nitrogen, and the dissolved oxygen in the drug solution was reduced to about 4.0 mg / l, and then filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampule without replacing the inside of the container with nitrogen, and was closed as it was. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in drug solution: 4.0mg / l Oxygen in space: 20v / v% pH of drug solution: 3.5 Buffer: 0.001mol / l tartrate buffer

Control Example 2 0.15 g of tartaric acid was added to about 700 ml of water for injection while stirring to dissolve it, and further, about 30 ml of a 0.02 mol / l aqueous sodium hydroxide solution was added.
Was added. 1g of nicardipine hydrochloride with stirring
And dissolved. After confirming dissolution, sodium chloride 8.9 g
After adding water for injection, add 1000
ml, and the pH of the solution was confirmed to be about 3.5.
Next, oxygen dissolved in the solution was replaced with nitrogen, and the dissolved oxygen in the drug solution was reduced to about 2.0 mg / l, and then filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampule without replacing the inside of the container with nitrogen, and was closed as it was. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in drug solution: 2.0mg / l Oxygen in space: 20v / v% pH of drug solution: 3.5 Buffer: 0.001mol / l tartrate buffer

Control Example 3 Lot. No. A114Y01 (Severe test) of 10 mg of perdipine injection (Yamanouchi Pharmaceutical Co., Ltd .; containing sorbitol as a stabilizer)
And Lot. No. B019Y01 (accelerated test). PH of chemical solution: 3.5 Buffer solution: none

Example 4 0.030 g of tartaric acid was dissolved in about 80 ml of water for injection, and 100 mg of nicardipine hydrochloride was added and dissolved with stirring. After adding 890 mg of sodium chloride to this solution and dissolving with stirring,
About 2 ml of 0.01 mol / l sodium hydroxide aqueous solution was added, and water for injection was added to make exactly 100 ml, and it was confirmed that the pH was about 3.0. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
Filtration was performed using a 0.22 μm filter. 10.5 ml of this liquid
Was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less, and then closed. . Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in drug solution: 4.0mg / l Oxygen amount in space: 2v / v% or less pH of drug solution: 3.0 Buffer: 0.002mol / l tartrate buffer

Example 5 0.015 g of tartaric acid was dissolved in about 80 ml of water for injection, and 100 mg of nicardipine hydrochloride was added and dissolved while stirring. After adding 890 mg of sodium chloride to this solution and dissolving with stirring,
About 12 ml of 0.01 mol / l sodium hydroxide aqueous solution was added, and water for injection was added to make exactly 100 ml, and it was confirmed that the pH was about 4.0. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
Filtration was performed using a 0.22 μm filter. 10.5 ml of this liquid
Was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less, and then closed. . Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in chemicals: 4.0 mg / l Oxygen in space: 2 v / v% or less pH of chemicals: 4.0 Buffer: 0.001 mol / l tartrate buffer

Control Example 4 To about 80 ml of water for injection, 1.5 g of tartaric acid was added with stirring to dissolve. Nicardipine hydrochloride 100mg with stirring
550 mg of sodium chloride, and the mixture was dissolved by stirring.Then, water for injection was added to make exactly 100 ml.
It was confirmed that H was about 2.0. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
After that, the mixture was filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content of the space to 2 v / v%.
After the following, it was closed. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen amount in chemical solution: 4.0mg / l Oxygen amount in space: 2v / v% or less pH of chemical solution: 2.0 Buffer solution: none

Control Example 5 To about 80 ml of water for injection, 0.15 g of tartaric acid was added with stirring to dissolve. Nicardipine hydrochloride 100m with stirring
g, dissolve, add 870 mg of sodium chloride, dissolve with stirring, add water for injection to make exactly 100 ml, p
It was confirmed that H was about 2.5. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
After that, the mixture was filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content of the space to 2 v / v%.
After the following, it was closed. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in chemicals: 4.0mg / l Oxygen in space: 2v / v% or less pH of chemicals: 2.5 Buffer: none

Control Example 6 0.015 g of tartaric acid was dissolved in about 80 ml of water for injection, and 100 mg of nicardipine hydrochloride was added and dissolved while stirring. After adding 890 mg of sodium chloride to this solution and dissolving with stirring,
About 16 ml of 0.01 mol / l sodium hydroxide aqueous solution was added, and water for injection was added to make exactly 100 ml, and it was confirmed that the pH was about 4.5. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
Filtration was performed using a 0.22 μm filter. 10.5 ml of this liquid
Was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less, and then closed. . Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in drug solution: 4.0 mg / l Oxygen in space: 2 v / v% or less pH of drug solution: 4.5 Buffer: 0.001 mol / l tartrate buffer

Control Example 7 0.015 g of tartaric acid was dissolved in about 80 ml of water for injection, and 100 mg of nicardipine hydrochloride was added and dissolved with stirring. After adding 890 mg of sodium chloride to this solution and dissolving with stirring,
About 18 ml of a 0.01 mol / l aqueous sodium hydroxide solution was added, and water for injection was added to make exactly 100 ml, and it was confirmed that the pH was about 5.0. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
Filtration was performed using a 0.22 μm filter. 10.5 ml of this liquid
Was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less and then closed. . Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in chemicals: 4.0 mg / l Oxygen in space: 2 v / v% or less pH of chemicals: 5.0 Buffer: 0.001 mol / l tartrate buffer

Example 6 To about 80 ml of water for injection, 0.15 g of tartaric acid was added and dissolved with stirring, and 43 mg of sodium hydroxide was further dissolved with stirring. To this solution, 100 mg of nicardipine hydrochloride was added and dissolved while stirring, and 840 mg of sodium chloride was further added to dissolve with stirring.Then, water for injection was added to make exactly 100 ml, and the pH was adjusted to about 100 ml.
I confirmed that it was 3.5. Next, oxygen dissolved in the solution was replaced with nitrogen, and the dissolved oxygen in the drug solution was reduced to about 4.0 mg / l, and then filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less. Later, it was closed. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in drug solution: 4.0mg / l Oxygen content in space: 2v / v% or less pH of drug solution: 3.5 Buffer: 0.01mol / l tartrate buffer

Example 7 To about 700 ml of water for injection, 0.075 g of tartaric acid was added and dissolved while stirring, and about 6 m of 0.02 mol / l aqueous sodium hydroxide solution was further added.
l was added. 1g of nicardipine hydrochloride with stirring
And dissolved. After confirming dissolution, sodium chloride 8.9 g
After adding water for injection, add 1000
ml, and the pH of the solution was confirmed to be about 3.5.
Next, the oxygen dissolved in the solution was replaced with nitrogen, and the dissolved oxygen in the drug solution was reduced to about 4.0 mg / l, and then filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less. Later, it was closed. Then 121 ° C
For 20 minutes to give an injection. Dissolved oxygen amount in chemical solution: 4.0mg / l Oxygen amount in space: 2v / v% or less pH of chemical solution: 3.5 Buffer: 0.0005mol / l tartrate buffer

Example 8 To about 80 ml of water for injection, 1.5 g of tartaric acid was added with stirring and dissolved, and 430 mg of sodium hydroxide was further dissolved with stirring. To this solution, 100 mg of nicardipine hydrochloride was added and dissolved while stirring. After confirming the dissolution, add 340 mg of sodium chloride, dissolve with stirring, add water for injection to make exactly 100 ml, and adjust the pH.
Was about 3.5. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
After that, the mixture was filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content of the space to 2 v / v%.
After the following, it was closed. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen in drug solution: 4.0mg / l Oxygen content in space: 2v / v% or less pH of drug solution: 3.5 Buffer: 0.1mol / l tartrate buffer

EXAMPLE 9 Water for injection was added to 0.105 g of citric acid to make up to 500 ml to prepare a citric acid solution. In addition, water for injection was added to 0.537 g of disodium hydrogen phosphate dodecahydrate to make up to 50 ml to obtain a disodium hydrogen phosphate solution. 180 ml of citric acid solution and 2 ml of disodium hydrogen phosphate solution were added, and it was confirmed that the pH was about 3.5. Nicardipine hydrochloride 10
0 mg was added and dissolved. After confirming dissolution, sodium chloride 9
After adding 00 mg and dissolving with stirring, the same buffer was further added to make exactly 100 ml, and it was confirmed that the pH of the drug solution was about 3.5. Next, oxygen dissolved in the solution was replaced with nitrogen, and the dissolved oxygen in the drug solution was reduced to about 4.0 mg / l, and then filtered using a filter having a diameter of 0.22 μm. 10.5 ml of this solution was filled in a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less. Later, it was closed. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen amount in chemical solution: 4.0 mg / l Oxygen amount in space: 2 v / v% or less pH of chemical solution: 3.5 Buffer solution: 0.001 mol / l citric acid / disodium hydrogen phosphate buffer solution

Example 10 Water for injection was added to 0.105 g of citric acid to make 500 ml to prepare a citric acid solution. Further, water for injection was added to 0.588 g of sodium citrate to make 100 ml, and water for injection was further added to 5 ml of this liquid to make 100 ml, thereby obtaining a sodium citrate solution. 170 ml of citric acid solution and 30 ml of sodium citrate solution were added, and it was confirmed that the pH was about 3.5. This liquid 8
To 0 ml, 100 mg of nicardipine hydrochloride was added and dissolved. After confirming dissolution, add 890 mg of sodium chloride and dissolve with stirring.
A buffer solution was added to make exactly 100 ml, and it was confirmed that the pH of the drug solution was about 3.5. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
The solution was filtered using a filter having a diameter of 0.22 μm. This liquid 10.
5 ml was filled into a brown ampoule in which the air in the ampoule was replaced with nitrogen, and then the space above the injection solution in the ampoule was replaced with nitrogen to reduce the oxygen content in the space to 2 v / v% or less, and then closed. did. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. Dissolved oxygen amount in chemical solution: 4.0 mg / l Oxygen amount in space: 2 v / v% or less pH of chemical solution: 3.5 Buffer: 0.001 mol / l citrate buffer

Control Example 8 About 400 ml of water for injection was heated to 60 ° C., and 0.5 g of nicardipine hydrochloride and 25 g of D-sorbitol were added thereto with stirring to dissolve. After the solution was cooled to room temperature, the pH was adjusted to 3.5 using 0.1 mol / l hydrochloric acid. Water for injection was added to this solution to make exactly 500 ml, and it was confirmed that the pH of the drug solution was about 3.5. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
Filtration was performed using a μm filter. 10.5 ml of this solution
The air in the ampoule was filled with a brown ampoule substituted with nitrogen, and the space above the injection solution in the ampoule was post-substituted with nitrogen to reduce the oxygen content of the space to 2 v / v% or less, and then closed. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. 5% D-sorbitol-containing dissolved oxygen in drug solution: 4.0 mg / l Oxygen content in space: 2 v / v% or less pH of drug solution: 3.5 Buffer solution: none

Control Example 9 About 400 ml of water for injection was heated to 60 ° C., and 0.5 g of nicardipine hydrochloride and 25 g of D-sorbitol were added thereto with stirring to dissolve. After the solution was cooled to room temperature, the pH was adjusted to 3.5 using 0.1 mol / l hydrochloric acid. Water for injection was added to this solution to make exactly 500 ml, and it was confirmed that the pH of the drug solution was about 3.5. Next, the oxygen dissolved in the solution is replaced with nitrogen, and the dissolved oxygen in the drug solution is reduced to about 4.0 mg / l.
Filtration was performed using a μm filter. 10.5 ml of this solution
The container was filled in a brown ampule without purging with nitrogen, and the container was closed as it was. Then, the mixture was sterilized at 121 ° C. for 20 minutes to give an injection. 5% D-sorbitol-containing dissolved oxygen in drug solution: 4.0mg / l Oxygen amount in space: 20v / v% pH of drug solution: 3.5 Buffer: none

Test Example 1 Severe test 1) Test conditions For sample groups having different amounts of oxygen in the ampoule, pH of chemical solution, concentration of buffer solution, type of buffer solution, or presence or absence of sorbitol addition, 100 ° C. For 168 hours (7 days).

2) Evaluation method The amount of nicardipine hydrochloride, the amount of dissolved oxygen and the pH of each preparation were measured before and after storage. From the obtained results, the residual ratio of nicardipine hydrochloride after storage relative to that before storage (%) was calculated, and the ratio (%) of the residual ratio of each preparation to the residual ratio of Control Example 3 (Perdipine injection, manufactured by Yamanouchi Pharmaceutical Co., Ltd.). , Stability was evaluated.

Method for quantifying nicardipine hydrochloride: Quantification of nicardipine hydrochloride was performed by high performance liquid chromatography (HPLC) under the following conditions. (HPLC analysis conditions) Column: Nucleosyl 300-5C18 (250 x 4 mm) Column temperature: 40 ° C Mobile phase: Methanol: 0.01 mol / l potassium dihydrogen phosphate solution = 18: 7 Detection wavelength: UV254 nm

3) Results The results are shown in Tables 1 to 6.

A. Comparison by difference of oxygen content in ampoule

[0042]

[Table 1]

From the results in Table 1, it is apparent that the product of Comparative Example 3 was apparently stable with respect to the change with time in pH, but the pH was slightly increased from the change in pH shown in Table 2. It can be seen that the pH has dropped later. This is due to the fact that pH fluctuations are caused not only by alkali elution from the container but also by polyhydric alcohol decomposed products (organic acids) generated by decomposing saccharides, which are the raw materials of polyhydric alcohols, under acidic hydrochloric acid. It seems to be due to.

[0044]

[Table 2]

B. Comparison by pH difference of chemical solution

[0046]

[Table 3]

C. Comparison by differences in buffer concentration

[0048]

[Table 4]

D. Comparison of different buffer types

[0050]

[Table 5]

E. Comparison with drugs with sorbitol

[0052]

[Table 6]

Test Example 2 The pH and the dissolved oxygen concentration of the drug solution after the severe test (100 ° C., 168 hours) were evaluated.

[0054]

[Table 7]

Test Example 3 Using Examples 1, 3, 6, 8, and 10 and Control Examples 3, 8, and 9, the dissolution of the chemical solution after a severe test (100 ° C., 168 hours) was visually observed. . As a result, all of the control examples were white and turbid due to crystallization of the composition components, whereas all of the examples had no turbidity and maintained transparency.

Test Example 4 Accelerated Test The residual rate of nicardipine chloride and fluctuation of pH during the effective period as a drug were evaluated by the following accelerated test.

1) Test conditions Each sample was stored in a thermostat at 40 ° C. for 6 months.

2) Evaluation method In the same manner as in Test Example 1 (severe test), the amount and pH of nicardipine hydrochloride before and after storage of each preparation were measured.
Nicardipine hydrochloride residual rate after storage compared to before storage (%)
Was calculated. In addition, a known degradation product of nicardipine hydrochloride [2- (N-benzyl-N-methylamino)
ethyl methyl-2,6-dimethyl-4- (3-nitrophenyl) -pyridi
ne-3,5-dicarboxylate hydrochloride] and the total amount of decomposed products were also compared.

3) Results Table 3 shows the changes in dissolved oxygen and pH and the residual ratio of nicardipine hydrochloride, and Table 4 shows the amounts of known decomposed products and total decomposed products contained in the preparation after 6 months. In Table 4, the amount of decomposed product (%) was calculated from the total peak area including nicardipine and the decomposed product peak area.

[0060]

[Table 8]

[0061]

[Table 9]

[0062]

EFFECT OF THE INVENTION The liquid preparation containing nicardipine hydrochloride of the present invention comprises
Without using D-sorbitol, which has safety issues,
The expected concentration can be maintained without causing deterioration or precipitation even after long-term storage. In addition, since D-sorbitol is not used, it does not generate D-sorbitol-derived degradation products and should be administered to patients with hypotonic dehydration and hereditary fructose intolerance, for which D-sorbitol is contraindicated. It is a highly safe formulation for emergency medical care.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA12 BB11 CC11 DD23D DD42Z FF65 FF67 4C086 AA01 BC26 GA13 MA02 MA03 MA05 MA09 MA17 MA66 NA03 NA06 ZA39 ZA40 ZA42 ZC50

Claims (4)

[Claims] 1. Nicardipine hydrochloride is dissolved in a buffer of 0.0001 to 0.1 mol / l, the pH is in the range of 3.0 to 4.5, and the dissolved oxygen in the drug solution after treatment at 100 ° C. for 168 hours is reduced. A liquid preparation containing nicardipine hydrochloride, which is not more than 3 mg / l. 2. The liquid preparation containing nicardipine hydrochloride according to claim 1, wherein the buffer is a tartrate buffer or a citrate buffer. 3. The composition according to claim 1, which further comprises a tonicity agent.
Or the liquid preparation containing nicardipine hydrochloride according to 2. 4. The nicardipine hydrochloride-containing preparation according to claim 1, which is an ampoule.