JPH05139971A - Isosorbide nitrate injection - Google Patents

Abstract

PURPOSE:To provide the subject stable injection containing isosorbide nitrate and at least one kind of component selected from cellulose derivative, gelatin, polyoxyethylene hardened castor oil, glycyrrhetin, albumin, etc., free from precipitation of crystal and useful as an antianginal agent, etc. CONSTITUTION:Isosorbide nitrate of formula registered in the Japanese Pharmacopoeia is mixed in injection water, dissolved by heating at about 80 deg.C in a water-bath to obtain a solution having an isosorbide nitrate concentration of 0.05-0.1W/V% and compounded with one or more kinds of additives such as a cellulose derivative (e.g. methylcellulose) having a concentration of 0.0005-0.1%, gelatin of 0.01-1.0% concentration, polyoxyethylene hardened castor oil of 0.5-10.0% concentration, glycyrrhetin of 0.001-0.1% concentration and albumin of 0.005-0.2% concentration. The obtained stable isosorbide nitrate injection is free from precipitation of crystal even at a concentration twice the critical concentration of the conventional injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a stable injectable preparation containing isosorbide nitrate.

[0002]

BACKGROUND ART Isosorbide dinitrate is a chemical substance that has a coronary artery dilating action and a venous volume vasodilating action and is used as an antianginal drug. The injectable preparation containing isosorbide nitrate is used as a medicine for acute heart failure and unstable angina, as a therapeutic medicine for intraoperative or postoperative management during cardiac surgery. Currently, as an injection containing isosorbide dinitrate, 0.05% of isosorbide dinitrate is used.
Although only W / V% concentration solutions are commercially available, injectable isosorbide nitrate is mostly used in emergencies. In the above target diseases, infusion of excessive amount of water is not preferable. Therefore, it is necessary to make the amount as small as possible, and therefore, a high concentration of isosorbide dinitrate injection is required. By the way, isosorbide dinitrate is a substance that is difficult to dissolve in water, and can dissolve up to a concentration of about 0.1 W / V% at room temperature, but 0.05 W / V%
If it exceeds, crystal precipitation occurs in the manufacturing process, so that its preparation was extremely difficult.

Isosorbide dinitrate is a medicinal substance listed in the Japanese Pharmacopoeia since 1976 and has a chemical structure represented by the following formula.

[0004]

[Chemical 1]

The present inventors have conducted various studies on a method for preparing an isosorbide dinitrate injection solution having a concentration exceeding 0.05 W / V%. As a result, when a single aqueous solution of isosorbide nitrate is stirred, crystals of isosorbide nitrate are precipitated, but one or more selected from cellulose derivative, gelatin, polyoxyethylene hydrogenated castor oil, glycyrrhizin and albumin are added to this nitric acid. It was found that when used by adding to an aqueous solution of isosorbide, precipitation of isosorbide nitrate crystals does not occur, and a stable isosorbide nitrate injection solution can be prepared.

[0006]

DISCLOSURE OF THE INVENTION According to the present invention, one or more selected from cellulose derivatives, gelatin, polyoxyethylene hydrogenated castor oil, glycyrrhizin and albumin are added to an injection solution containing isosorbide dinitrate as an active ingredient. The present invention provides a stable injectable preparation containing isosorbide nitrate.

The present invention will be described in detail below.

Among the components to be contained together with isosorbide dinitrate in the injectable composition of the present invention, the above cellulose derivative may be methyl cellulose or hydroxypropyl methyl cellulose.

Methylcellulose is an organic polymer substance listed in the Japanese Pharmacopoeia and composed of anhydrous glucose units having a molecular weight of 50 to 1500. Hydroxypropylmethyl cellulose having a molecular weight of about 86000 is listed in the Japanese Pharmacopoeia. The above-mentioned component, gelatin, is a linear polymer in which amino acids are linked by peptide bonds and has a molecular weight of 15,000.
˜250,000 induced proteins, which are listed in the Japanese Pharmacopoeia. The above-mentioned polyoxyethylene hydrogenated castor oil is listed in the Japanese Pharmacopoeia Standard for Pharmaceutical Ingredients and is widely used as a pharmaceutical additive. Glycyrrhizin is a substance in which two molecules of glucuronic acid are bound to glycyrrhetinic acid and is a substance used in various pharmaceuticals. The albumin is a protein derived from egg white or serum, which is also used in various pharmaceutical products.

Regarding the injectable composition of the present invention, the amounts of various components to be contained together with isosorbide dinitrate will be described below. Concentration of isosorbide dinitrate 0.05
The concentration of the cellulose derivative is 0.0005 W / V% to 0.1 W / V%, preferably 0.001 W / V% to 0.02 W / V%, relative to W / V% to 0.1 W / V%, gelatin. Is 0.01 W / V% to 1.0 W / V%, preferably 0.05 W / V% to 0.1 W / V%, and the concentration of polyoxyethylene hydrogenated castor oil is 0.5 W / V% to 10%. 0.0W
/ V%, preferably 0.8 W / V% to 1.2 W / V%,
Glycyrrhizin concentration is 0.001W / V% -0.1W
/ V%, preferably 0.005W / V% to 0.02W /
The concentration of V% and albumin is 0.005 W / V% to 0.2
W / V%, preferably 0.01 W / V% to 0.1 W / V
%. Below the lower limit of the above concentration range, the effect of preventing the precipitation of isosorbide nitrate is not sufficiently observed, and above the upper limit, no further improvement in the effect is observed.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Experimental Examples of the injectable composition according to the present invention.

Example 1 An injection was prepared according to the following formulation. (Formulation) Isosorbide dinitrate 1 g Methylcellulose 10 mg Sodium chloride 9 g Water for injection Appropriate amount 1 liter (Preparation method) 1 g of isosorbide dinitrate is mixed with water for injection and dissolved by heating in a water bath at about 80 ° C., methylcellulose (trade name Metroze) SM-15 manufactured by Shin-Etsu Chemical) 10
After adding mg and 9 g of sodium chloride and thoroughly stirring, water for injection at about 80 ° C. was added, and after cooling, water for injection was added to make a total volume of 1 liter, and the mixture was dispensed into ampoules and melt-sealed.

Example 2 An injection was prepared according to the following formulation. (Formulation) Isosorbide dinitrate 1 g Gelatin (acid treatment) 100 mg Sodium chloride 9 g Water for injection Appropriate amount 1 liter (Preparation method) 1 g of isosorbide dinitrate is mixed with water for injection and dissolved by heating in a water bath at about 80 ° C, gelatin (Acid treatment type made by Nitta Gelatin) 100 mg and 9 g of sodium chloride were added, and after sufficiently stirring, water for injection at about 80 ° C was added, and after cooling, water for injection was added to bring the total volume to 1 liter. It was poured and closed.

Example 3 An injection was prepared according to the following formulation. (Prescription) Isosorbide dinitrate 1 g Polyoxyethylene hydrogenated castor oil 60 10 g Sodium chloride 9 g Water for injection Total amount 1 liter (Preparation method) Isosorbide dinitrate 1 g polyoxyethylene hydrogenated castor oil (trade name Nikkor HCO-60 Nippon Chemicals Co., Ltd.) To 10 g, dissolve by heating in an aqueous solution at about 80 ° C, stir well, add 9 g of sodium chloride and water for injection heated to about 80 ° C, and after cooling, add water for injection to bring the total amount to 1 It was made up to a liter, dispensed into an ampoule, and sealed.

Example 4 An injection was prepared according to the following formulation. (Prescription) Isosorbide dinitrate 1 g Glycyrrhizin 100 mg Sodium chloride 9 g Water for injection Appropriate amount 1 liter (Preparation method) 1 g of isosorbide dinitrate is mixed with water for injection, heated and dissolved in a water bath at about 80 ° C to dissolve glycyrrhizin (trade name Nikkor) Glycyrrhizic acid (manufactured by Japan Chemicals Co., Ltd.) 100 mg and sodium chloride 9 g were added, and after sufficiently stirring, water for injection at about 80 ° C. was added, and after cooling, water for injection was added to make a total volume of 1 liter and dispensed into ampoules. , Closed.

Example 5 An injection was prepared according to the following formulation. (Prescription) Isosorbide dinitrate 1 g Albumin 500 mg Sodium chloride 9 g Water for injection Appropriate amount 1 liter (Preparation method) Mix 1 g of isosorbide nitrate with water for injection, dissolve by heating in a water bath at about 80 ° C, and cool to about 40 ° C. And albumin (human serum albumin manufactured by Sigma)
500 mg and 9 g of sodium chloride were added, and after uniformly stirring, water for injection at about 40 ° C. was added, and after cooling, water for injection was added to make a total volume of 1 liter, and the mixture was dispensed into ampoules and melt-sealed.

Comparative Example An injection was prepared according to the following formulation. (Formulation) Isosorbide dinitrate 1 g Hydroxyethyl cellulose 30 mg Sodium chloride 9 g Water for injection Appropriate amount 1 liter (Preparation method) 1 g of isosorbide dinitrate is mixed with water for injection and dissolved by heating in a water bath at about 80 ° C., hydroxyethyl cellulose (commodity) 30 mg of name HEC / SE550 Daicel) and 9 g of sodium chloride were added, and after uniformly stirring, water for injection at about 80 ° C. was added, and after cooling, water for injection was added to make a total volume of 1 liter, which was dispensed into ampoules, It closed.

Experimental Example 1 In Examples 1 to 3 and Comparative Example, tests were conducted by the following method in order to determine the dissolution state of the isosorbide dinitrate solution by the degree of crystal precipitation.

1) Samples Each solution was taken out from each ampoule obtained in Example 1, Example 2, Example 3 and Comparative Example and used as a sample.

2) Test method Each sample is tested in accordance with the following.

Precipitation by stirring: to 100 ml of sample,
A stirrer (3 cm) was added, and the solution was vigorously stirred (about 600 rpm) for 1 hour while maintaining the temperature of the solution at room temperature. After stirring
20 ml of a sample was collected and filtered using a membrane filter (diameter 13 mm) having a pore size of 0.2 μm to remove precipitated isosorbide nitrate. Remove the first 10 ml of the filtrate,
Using the following filtrate, the content of isosorbide nitrate in the liquid was measured by liquid chromatography.

Measurement conditions Detector: Ultraviolet absorptiometer (measurement wavelength 220n
m) Column: A stainless steel tube having an inner diameter of 4 mm and a length of 15 cm was filled with 5 to 10 μm octadecylsilylated silica gel. Column temperature: Constant temperature around 40 ° C Mobile phase: Water / acetonitrile mixture (9:11)

Precipitation by liquid circulation: An automatic dispenser (manufactured by Toyo Riko Co., Ltd.) equipped with a 10 ml glass syringe was used to create a circulation system in which the suction port and the discharge port were put in the same container, and a 100 ml sample was prepared. Was put in a container and operated for 5 hours while keeping the liquid temperature at room temperature. Next, 20 ml of the sample is sampled and a membrane filter with a pore size of 0.2 μm (diameter 13 m
m) was filtered to remove the precipitated isosorbide dinitrate. The content of isosorbide dinitrate in the liquid was measured by liquid chromatography under the same conditions as in the first filtrate except that 10 ml was removed.

3) Results Table 1 shows the state (property) of the solution after the test and the residual ratio of isosorbide dinitrate.

[0025]

[Table 1]

The residual ratio is a ratio when the content of isosorbide nitrate in the liquid in the ampoule obtained in Examples 1 to 3 and Comparative Example is 100%. (Residual rate = content before test / content after test × 100)

Precipitation by stirring In the comparative example, the precipitation was clearly observed and the content was reduced, but in the examples 1 to 3, no precipitation was observed and the content was not reduced.

Precipitation by Liquid Circulation In the comparative example, precipitation was clearly observed and the content was reduced, but in Examples 1 to 3, no precipitation was observed and no decrease in content was observed.

Experimental Example 2 The stability of the isosorbide dinitrate solution was observed for the ampoules obtained in Examples 1 to 3 and Comparative Example.

1) Specimens Each solution was taken out from the ampoules obtained in Examples 1, 2 and 3, and Comparative Examples and used as specimens.

2) Test Method The following test was conducted on each sample.

(I) Storage conditions: left at 40 ° C. for 3 months, left at room temperature for 6 months, left alternately at 5 ° C. and room temperature for 1 month

(Ii) Measuring method Properties: The presence or absence of crystals and the color tone were observed with a magnifying glass. Content: The content of isosorbide dinitrate in the sample was measured by liquid chromatography under the same conditions as in Experimental Example 1.

3) Table 2 shows the results of the stability test.

[0035]

[Table 2]

The residual ratio is a ratio when the content of isosorbide dinitrate existing in the liquid in the ampoule preparations obtained in Examples 1 to 3 and Comparative Example is 100%. (Residual rate = content before test / content after test × 100)

After standing at 40 ° C. for 3 months, no precipitation was observed in any of the samples and no decrease in content was observed.

After standing for 6 months at room temperature, no precipitation was observed in any of the samples, and no decrease in content was observed.

After being left at 5 ° C. and room temperature alternately for 1 month, precipitation was clearly observed in the comparative example and the content was reduced, but no precipitation was observed in Examples 1 to 3, and the content was also reduced. I couldn't do it.

[0040]

INDUSTRIAL APPLICABILITY With the injection according to the present invention, no crystal precipitation of isosorbide dinitrate is observed against impact by stirring or liquid circulation, and crystal precipitation and decomposition do not occur even in a stability observation test under severe conditions. I was not able to admit.

The injectable composition according to the present invention can be used for lubrication without lowering the content due to precipitation or clogging of the filter during the manufacturing process, and is currently in use. It is possible to provide an injection having a concentration twice that of the injection (0.05 W / V%) (0.1 W / V%), which is extremely useful for a patient with a target disease in which an overdose of water is undesirable. It is a thing.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location A61K 47/42 G 7329-4C 47/44 G 7329-4C

Claims (1)

[Claims] 1. An injectable preparation comprising isosorbide dinitrate and one or more selected from a cellulose derivative, gelatin, polyoxyethylene hydrogenated castor oil, glycyrrhetin and albumin.