KR100188318B1 - Stabilized injection and method of stabilizing injection - Google Patents

Abstract

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1, characterized in that the present invention is formulated with a stabilizer against light. A stabilized injectable agent and a stabilizing method comprising 4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient.

One or two or more light stabilizers selected from sulfites, sulfites, ascorbic acids, L-cysteine or acid addition salts thereof, thioglycolic acid or metal salts thereof, ethylenediamine, salicylic acid or metal salts thereof, or phenols or derivatives thereof Coloring prevention appears by compounding.

Description

[Name of invention]

Stabilized Injections and Stabilization of Injections

Detailed description of the invention

[Technical Field]

The present invention has a potent and selective serotonin-3 receptor antagonistic action and is useful as an agent for improving or treating annoyance, vomiting, anorexia associated with administration of anti-malignant tumors such as cisplatin, etc. (±) -6-chloro-3, To stabilized injection of 4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride and to injection of the compound containing injection It is about.

[Background]

Japanese Unexamined Patent Application Publication No. Hei 2-28182 has a potent and selective serotonin-3-receptor antagonistic action, and is useful as an agent for improving or treating discomfort, vomiting, anorexia associated with the administration of anti-malignant tumor agents such as cisplatin, etc. Expected (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride (Hereinafter, it may also be referred to as the present compound) is described, and it is disclosed that the pharmaceutical form is used as a parenteral agent such as oral preparations such as tablets and injections.

However, it has been found that the present compound is particularly inferior in stability in the state of an aqueous solution or suspension, easily photolyzed and markedly changed in color. Such a liquid formulation is generally devised to prevent photolysis by coating with a light shielding container. According to this method, photodegradation can be suppressed during the distribution or preservation of medicines, but when used in a clinical place, it is often left in a state easily exposed to light. It's not hard to imagine that things will happen so often.

Therefore, the present invention provides a stable (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H- which suppresses decomposition by light, especially color change. It is an object to provide an injection containing 1,4-benzoxazine-8-carboxamide monohydrochloride and a stabilization method.

[Initiation of invention]

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, the present inventors came to complete this invention. That is, the present invention is characterized in that the combination of the stabilizer against light (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H- Stabilized injectables comprising 1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient and (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N as an active ingredient A stabilizing method for an injection is characterized by incorporating a stabilizer against light into an injection containing 3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride.

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8 as an active ingredient compound used in the present invention -Carboxamide monohydrochloride is 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4, as described in Japanese Patent Application Laid-Open No. 2-28182. Reactive derivatives of benzoxazine-8-carboxylic acid (such as acid chloride) and 3-aminoquinuclidine are preferably prepared by reacting in a solvent inert to the reaction in the presence of a deoxidizer, followed by hydrochloride.

In addition, as a stabilizer against light used in the present invention, sulfite, sulfite ascorbate, L-cysteine or acid addition salts thereof, thioglycolic acid or metal salts thereof, ethylenediamine, salicylic acid or metal salts thereof, or phenol or derivatives thereof It is 1 type (s) or 2 or more types chosen from. Among them, sulfite is preferred, and examples thereof include pyrosulfite and hydrogen sulfite salts, and examples thereof include sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium pyrosulfite and potassium pyrosulfite. In particular, sodium pyrosulfite (sodium hydrogen sulfite containing this product can also be used) is excellent in suppressing a coloring change. The blending amount of such stabilizer varies depending on the type of stabilizer, but is usually about 0.001 to about 5 parts by weight, preferably about 0.01 to about 2 parts by weight, based on 1 part by weight of the present compound, which is an active ingredient.

The stabilized injectable agent of the present invention may further contain an additive for injectables. For example, an osmotic pressure adjusting agent, a pH adjusting agent, a preservative, and a non-permeable agent are used as the additive. Among these, as the osmotic pressure regulator, electrolytes such as sodium chloride, amino acids such as glycine, sugars such as glucose, and / or polyols such as mannitol, and the like, and the compounding amount thereof is preferably used at a concentration of isotonic concentration or less, and is usually an injection. About 5% weight / volume part of the total amount is good, and about 0.9% weight / volume part of the case of using sodium chloride. In addition, as a pH adjuster, it is preferable to adjust final pH to about 3-5, and acids, such as hydrochloric acid, a citric acid, an acetic acid, lactic acid, are used. Alkali, such as sodium hydroxide, can also be used as needed.

Injectable preparations of the present invention are prepared by dissolving the above additives, such as the present compound, stabilizer against light, osmotic pressure adjusting agent and pH adjusting agent, in distilled water for injection, filtering, filling in a container for injection, and melting sealing. It is preferable to perform filtration in nitrogen atmosphere, and it is preferable that the container for filling is also wash | cleaned previously with nitrogen. In addition, after filling the solution with a container for injection, the air in the container is preferably nitrogen-substituted, and after melting and sealing, it is preferable to sterilize by heating. Injectable preparations thus obtained are stable to light exposure and exhibit an excellent stabilizing effect, in particular that the color change is suppressed. It was also confirmed that there was no hemolysis and no crystal precipitation in serum, and there was no problem in use as an injection. When it is stored in a light-shielding container as a final formulation, for example, the stabilization effect to light can be further improved.

The stabilized injection of the present invention thus obtained exhibits excellent serotonin-3 receptor antagonism and improves or treats discomfort, vomiting, anorexia, or chronic gastritis associated with the administration of an anti-malignant tumor such as cisplatin in humans. And digestive diseases such as irritable bowel syndrome.

When the stabilized injection of the present invention is used for amelioration or treatment of the disease, it can be safely administered to the patient by the route of intravenous administration, subcutaneous administration, intramuscular administration and the like. The dosage is usually from about 0.1 mg to about 50 mg, preferably from about 1 mg to about 30 mg, per day as an active ingredient (free base).

Best Mode for Carrying Out the Invention

Hereinafter, although an Example demonstrates this invention in detail, it cannot be overemphasized that this invention is not limited to these.

Example 1

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride 10 g, fatigue 0.5 g of sodium sulfite and 18 g of sodium chloride previously heat-sterilized at 250 ° C. for 30 minutes or more are dissolved in an appropriate amount of distilled water for injection, and the total amount is adjusted to 2,000 ml. The obtained solution was filtered through a membrane filter (pore diameter 0.45 mu m) under a nitrogen atmosphere, filled with 2 ml each of 2 ml volume ampoules, and the air was removed by nitrogen substitution, melt-sealed, and sterilized at 115 ° C. for 30 minutes. .

Example 2

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride 5 g, L -2 g of cysteine and 9 g of sodium chloride are dissolved in an appropriate amount of distilled water for injection, hydrochloric acid is added to adjust to pH 4, and a total amount of a solution of 1,000 ml is prepared. In the same manner as in Example 1, the solution was placed in an ampoule and sterilized to obtain 2 ml of injection.

Example 3

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride 5 g, thio A total amount of 1,000 ml of injection was prepared in the same manner as in Example 1 using an appropriate amount of 3 g of sodium glycolate, 9 g of sodium chloride, and hydrochloric acid and distilled water for injection. This solution is placed in an ampoule in the same manner as in Example 1 and sterilized to obtain 2 ml of injection.

Example 4

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride 5 g, ethylene A total amount of 1,000 ml of injection was prepared in the same manner as in Example 1 using 5 g of diamine, 9 g of sodium chloride, hydrochloric acid, and distilled water for injection, respectively, to thereby obtain a 2 ml injection.

Example 5

A 2 ml injection is obtained in the same manner as in Example 1 except that ascorbic acid, sodium salicylate or phenol is used as a stabilizer against light.

Next, the stabilizing effect of the injection of this invention is demonstrated by an experimental example. The injection used in the experiment was an ampoule for injection of Examples 1 to 4, and the following prescription formulation was used as a comparative injection.

[Comparative prescription]

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride 5 g, chloride A solution of 1,000 ml in total was prepared in the same manner as in Example 1 using 9 g of sodium and an appropriate amount of distilled water for injection, followed by 2 ml of injection.

Experimental Example 1

The injections in the white ampoules of Examples 1 to 4 and Comparative Formulations were used for exposure to light for 1 hour under room light (about 700 lux), and then the appearance was visually observed. The results are shown in Table 1. In the same manner, exposure to light under room light (about 700 lux) for 7 hours was followed by measurement of absorbance at 400 nm and 503 nm by spectrophotometer. The results are shown in Table 2.

[Industry availability]

As is evident from the foregoing specification, particularly from the description of the Examples and Experimental Examples, the present invention provides stabilized injections of compounds having serotonin-3 antagonism and useful as a medicament and methods of stabilizing injections.

Claims (12)

(±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclein characterized by blending a stabilizer against one or more species of light selected from sulfites A stabilized injectable agent comprising diyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient. The injection of claim 1 wherein the sulfite is selected from sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium pyrosulfite, potassium pyrosulfite. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient A stabilized injectable agent comprising sodium pyrosulfite as a stabilizer against light. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient A method for stabilizing an injectable, characterized in that a compound containing a stabilizing agent for light, which is one or two or more selected from sulfite salts, is incorporated. The stabilizing method according to claim 6, wherein the sulfite is selected from sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium pyrosulfite, potassium pyrosulfite. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1 characterized by blending sodium pyrosulfite as a stabilizer against light A method for stabilizing injections containing, 4-benzoxazine-8-carboxamide monochloride. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclein characterized by blending a stabilizer against one or more species of light selected from sulfites Injectable agent which suppressed the coloring change of the diyl-2H-1, 4-benzoxazine-8-carboxamide monohydrochloride. The injection of claim 7, wherein the sulfite is selected from sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium pyrosulfite, potassium pyrosulfite. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient, An injection agent with suppressed color change, characterized by containing sodium pyrosulfite as a stabilizer against light. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8-carboxamide monohydrochloride as an active ingredient A method for suppressing color change of an injection, comprising blending an injection containing a stabilizer against light, which is one or two or more selected from sulfites. The method of inhibiting color change according to claim 10, wherein the sulfite is selected from sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, sodium pyrosulfite and potassium pyrosulfite. (±) -6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinucridinyl-2H-1 characterized by incorporating sodium pyrosulfite as a stabilizer against light Method for suppressing color change of, 4-benzoxazine-8-carboxamide monohydrochloride-containing injection.