JP2009280561A - Parenteral injection - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a parenteral injection of 3-methyl-1-phenyl-2-pyrazolin-5-one having excellent long-term stability even at a high concentration. <P>SOLUTION: The parenteral injection is characterized by comprising 1.0-100.0 mg/ml of the 3-methyl-1-phenyl-2-pyrazolin-5-one, and a solubilizing agent and/or a dissolution adjuvant, and a stabilizer. The solubilizing agent and/or the dissolution adjuvant is an amino aid and/or a salt thereof, and the amino acid is particularly preferably arginine, histidine, or lysine. The stabilizer is preferably selected from among sulfurous acid, hydrogen sulfite, pyrosulfurous acid, thioglycerol and thioglycolic acid, and salts thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an injection comprising 3-methyl-1-phenyl-2-pyrazolin-5-one (hereinafter referred to as Compound 1) as an active ingredient and excellent in long-term stability even at a high concentration.

  Compound 1 improves neurological symptoms, daily life movement disorders, and functional disorders associated with the acute phase of cerebral infarction by the action of scavenging free radicals and suppressing lipid peroxidation. In the administration of Compound 1, one ampule (30 mg / 20 mL ampule as Compound 1) is usually diluted with physiological saline once per adult, and intravenous drip infusion is required twice a day in the morning and evening.

  However, the use of a large ampule of 20 mL in a medical field is feared for adverse effects on aseptic operation because it takes time to extract a solution from the ampule and dilute with physiological saline, or at the time of ampule cut There are concerns about contamination of foreign objects caused by glass fragments and injury to fingers. In addition, the large volume is disadvantageous in terms of cost and space for transportation and storage in the physical distribution stage and medical institutions.

  In order to solve the above problems, it is conceivable to prepare a small-sized preparation that is easy to handle by developing a concentrated preparation of Compound 1, and further to change the container from an ampule to a vial. However, in any conventional technique, preparation of the preparation is difficult due to the problem of the solubility of Compound 1 in water (2 mg / mL or less) and the nitrogen replacement of the vial preparation cannot be performed stably. It was.

As a method for stabilizing Compound 1 in an aqueous solution, the aqueous solution of Compound 1 contains one or more selected from sulfites, bisulfites, and pyrosulfites and cysteines, and has a pH of 2.5 to 6. A pharmaceutical formulation characterized by being in the range of 0 is disclosed (Patent Document 1), but the Examples only have the result of a stability test when the concentration of Compound 1 is 2 mg / mL. There is no mention of stability. Moreover, since cysteine is used as an additive, there is a concern about the generation of related substances. As a technique for increasing the concentration, methods using ethanol as a solubilizer (Patent Documents 2 and 3) are disclosed. However, since these technologies also use a large amount of ethanol in the production process, the possibility of problems arising from various dangers (flammability, volatility, toxicity, irritation, etc.) of ethanol cannot be denied. Patent Document 2 discloses a prescription for stabilizing the preparation by adding a chelating agent (e.g., disodium ethylenediaminetetraacetate). The chelating agent contains calcium, which is an essential metal in the living body. There are concerns about safety, such as chelation, and it is not always preferable as a prescription for preparations. In view of the above, development of a high-concentration injection having high long-term storage stability and excellent preparation preparation is desired.
No. 7-121861 WO2002 / 092082 JP 2006-257020 A

Problems to be solved by the invention

  That is, an object of the present invention is to provide an injection of Compound 1 having excellent long-term stability even at high concentrations.

Means for solving the problem

  As a result of intensive studies to solve the above problems, the present inventors have prepared a high-concentration compound 1-containing solution by using amino acids and salts thereof as compound 1, and further a container filled with the solution. By replacing the inside with an inert gas, a highly stable injection of Compound 1 was found, and the present invention was completed.

で表される３−メチル−１−フェニル−２−ピラゾリン−５−オンを１．０ｍｇ／ｍＬ乃至１００．０ｍｇ／ｍＬ含有し、溶解剤及び／又は溶解補助剤、定化剤を含むことを特徴とする注射剤。２）溶解剤及び／又は溶解補助剤がアミノ酸及び／又はその塩である請求項１に記載の注射剤。３）アミノ酸がアルギニン、ヒスチジン、リジンから選ばれる請求項２記載の注射剤。４）アミノ酸の濃度が、１〜２００ｍｇ／ｍＬである請求項３に記載の注射剤。５）安定化剤が亜硫酸、亜硫酸水素、ピロ亜硫酸、チオグリセロール及びチオグリコール酸並びにそれらの塩から選ばれる請求項１から４に記載の注射剤。６）ｐＨが３乃至８であることを特徴とする請求項１から５に記載の注射剤。７）３−メチル−１−フェニル−２−ピラゾリン−５−オンを含有する溶液を充填する容器がガラス製又は樹脂製のアンプル、バイアル、シリンジ又はバッグである請求項６に記載の注射剤。８）容器の内面がシリコート処理又はサルファー処理された請求項７に記載の注射剤。９）容器の内部の空間を不活性ガスで置換することを特徴とする請求項７又は８に記載の注射剤等に関する。That is, the present invention
1) The following formula (1)

Containing 1.0 mg / mL to 100.0 mg / mL of 3-methyl-1-phenyl-2-pyrazolin-5-one represented by the formula: a solubilizing agent and / or a solubilizing agent and a qualifying agent. An injectable composition. 2) The injection according to claim 1, wherein the solubilizer and / or solubilizer is an amino acid and / or a salt thereof. 3) The injection according to claim 2, wherein the amino acid is selected from arginine, histidine, and lysine. 4) The injection according to claim 3, wherein the amino acid concentration is 1 to 200 mg / mL. 5) The injection according to any one of claims 1 to 4, wherein the stabilizer is selected from sulfite, hydrogen sulfite, pyrosulfite, thioglycerol, thioglycolic acid and salts thereof. 6) The injection according to any one of claims 1 to 5, wherein the pH is 3 to 8. 7) The injection according to claim 6, wherein the container filled with the solution containing 3-methyl-1-phenyl-2-pyrazolin-5-one is a glass or resin ampoule, vial, syringe or bag. 8) The injection according to claim 7, wherein the inner surface of the container is treated with silicoat or sulfur. 9) The injection or the like according to claim 7 or 8, wherein the space inside the container is replaced with an inert gas.

The invention's effect

  According to the present invention, it is possible to prepare a long-term stable preparation at a high concentration and a small volume of Compound 1, and it is possible to provide a simple and highly safe preparation that can be quickly handled in a medical field.

  In the present invention, when compound 1 is dissolved in water, a surfactant is used as a solubilizer and / or a solubilizing agent, a stabilizer is contained, and an isotonic agent, a pH adjuster, etc. are added as necessary. It is an injection.

  The injection of the present invention is usually prepared by adding a solubilizer and / or a solubilizing agent and a stabilizer such as sodium hydrogen sulfite to water for injection through nitrogen in advance, and dissolving Compound 1 at room temperature, as necessary. An isotonizing agent is added, it adjusts to desired pH with a pH adjuster, and the whole quantity is prepared with water for injection. This solution can be produced by filtration through a membrane filter, filling a suitable container, and subjecting it to a conventional heat sterilization treatment.

  The concentration of Compound 1 used for the injection of the present invention is 1.0 mg / mL to 100.0 mg / mL, preferably 1.5 mg / mL to 15.0 mg / mL, and 1.5 to 6.0 mg / mL. mL is more preferred.

  The solubilizer and / or solubilizer used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, and isoleucine. , Leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine and the like, and salts thereof, preferably arginine, histidine, lysine and salts thereof. These solubilizers and / or solubilizers can be used alone or in combination. The concentration of these solubilizers and / or solubilizers in the injection of the present invention is not particularly limited as long as it is a pharmaceutically acceptable range, but it is preferably 1 to 1 per one kind of solubilizer or solubilizer. 200 mg / mL, and a more preferable range is 10 to 50 mg / mL.

  The stabilizer used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, sulfite, pyrosulfite, hydrogen sulfite, citric acid, thioglycolic acid, thioglycerol, thiomalic acid, edetic acid , Ascorbic acid, butylhydroxyanisole and salts thereof, and sulfurous acid, hydrogen sulfite, pyrosulfurous acid, thioglycerol and thioglycolic acid and their salts are preferred. These stabilizers can be used alone or in combination.

  The pH adjuster used in the present invention is not particularly limited as long as it is usually physiologically acceptable, but for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, succinic acid, acetic acid, lactic acid Organic acids such as benzoic acid, and basic substances such as sodium hydroxide, phosphate, citrate, and the like, if necessary, hydrochloric acid, phosphoric acid, and citric acid are preferred. Moreover, the buffer generally used normally can also be used as a pH adjuster. These pH regulators can be used alone or in combination. The concentration of the pH adjusting agent is not particularly defined as long as the injection of the present invention is set to have a pH of 3.0 to 8.0, preferably pH 3.0 to 6.0.

  The injection of the present invention may further contain one or more usual additives in injectable preparations in addition to the above additives. Such additives include tonicity agents and the like.

  The isotonic agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sodium chloride, potassium chloride, fructose, glucose and the like, and these isotonic agents are used alone or in combination. be able to.

  The container used for the injection of the present invention is not particularly limited as long as it is for medical use, but generally used glass containers (glass containers), resin containers (for example, plastic containers), etc. These containers can be used and may be subjected to any treatment that is acceptable for medical use. Examples of such treatment include light shielding, silicoat treatment, sulfur treatment, and silicon coating. Examples of the container include ampoules, vials, syringes, bags, and the like. Resin containers can be made of olefin resin (eg, polyethylene, polypropylene, polybutene, etc.), polyester resin (eg, polyethylene terephthalate, polybutylene terephthalate, etc.), styrene, regardless of whether it is soft, hard, low density, or high density. Examples thereof include copolymers, acrylic resins, cycloolefin resins, polycarbonates, and the like, and copolymers or mixtures obtained by combining a plurality of these raw material components.

  In the above production process, in order to prevent oxidative decomposition of Compound 1, the head space (space part) in the container can be replaced with an inert gas such as nitrogen gas. Although it will not specifically limit if oxidative decomposition of can be prevented, Preferably it is 5% or less, More preferably, it is 3% or less. Moreover, the purified water used in the production process can be used by previously ventilating with an inert gas, or the above production process can be performed while the inert gas is vented.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, the scope of the present invention is not limited by the following Example.

  Example 1: 250 mg of arginine was dissolved in water for injection, 150 mg of compound 1 was added, the total amount was 50 mL, and the mixture was stirred at room temperature. After 1 hour, the dissolution state of Compound 1 was visually confirmed.

  Comparative Example: Alanine (Comparative Example 1), Arginine hydrochloride (Comparative Example 2), Cysteine (Comparative Example 3), Histidine (Comparative Example 4), Lysine hydrochloride (Comparative Example 5) instead of arginine of Example 1 Preparation using Phenylalanine (Comparative Example 6), Glycine (Comparative Example 7), Cysteine Hydrochloride (Comparative Example 8), and no amino acid added (Comparative Example 9) as in Example 1 did. One hour later, the dissolution state of edaravone was visually confirmed.

  From the above test results, it was confirmed that Compound 1 can be dissolved at room temperature by using arginine.

  Example 2: 500 mg of arginine, 200 mg of sodium bisulfite, and 300 mg of compound 1 were added to water for injection through nitrogen, dissolved at room temperature, adjusted to pH 4.0 with 1 mol / L hydrochloric acid, 100 mL. This solution was filtered through a 0.22 μm membrane filter, filled into 4.0 mL and 10.0 mL ampoules, the headspace was replaced with nitrogen, and the ampules were melted. This was sterilized at 121 ° C. for 20 minutes, and then subjected to a stability test at 60 ° C. for 2 weeks.

  Comparative Example 10: 1000 mg of arginine, 200 mg of sodium bisulfite, and 300 mg of edaravone were added to water for injection through nitrogen, and after dissolution, the pH was adjusted to 4.0 with 1 mol / L hydrochloric acid to make the total volume 100 mL. This solution was filtered through a 0.22 μm membrane filter, filled into 4.0 mL and 10.0 mL ampoules, the headspace was replaced with nitrogen, and the ampules were melted. This was sterilized at 121 ° C. for 20 minutes, and then subjected to a stability test at 60 ° C. for 2 weeks.

  Comparative Example 11: A stability test at 60 ° C. for 2 weeks was conducted in the same manner as in Example 2 using a commercial preparation containing Compound 1 (trade name “Radicut”, manufactured and sold by Mitsubishi Tanabe Pharma Corporation).

  From the above test results, in Example 2, the concentration of Compound 1 was 3 mg / mL and twice the existing commercial preparation (1.5 mg / mL), but there was no precipitation of Compound 1 and no change in pH, It was possible to prepare a preparation having a physiological pH close to that of Comparative Example 11 using a commercially available preparation and less related substances.

  That is, the injection according to the present invention can be easily adjusted at room temperature even at a high concentration and a small volume by using an amino acid as a solubilizing agent and / or a solubilizing agent and adding an antioxidant. It turned out that the compound 1 containing liquid agent excellent in the usability can be provided.

Claims (9)

The following formula (1)

Containing 1.0 mg / mL to 100.0 mg / mL of 3-methyl-1-phenyl-2-pyrazolin-5-one represented by the formula: a solubilizing agent and / or a solubilizing agent and a qualifying agent. An injectable composition. The injection according to claim 1, wherein the solubilizer and / or solubilizer is an amino acid and / or a salt thereof. The injection according to claim 2, wherein the amino acid is selected from arginine, histidine, and lysine. The injection according to claim 3, wherein the concentration of the amino acid is 1 to 200 mg / mL. The injection according to claims 1 to 4, wherein the stabilizer is selected from sulfite, hydrogen sulfite, pyrosulfite, thioglycerol and thioglycolic acid, and salts thereof. The injection according to any one of claims 1 to 5, wherein the pH is 3 to 8. The injection according to claim 6, wherein the container filled with a solution containing 3-methyl-1-phenyl-2-pyrazolin-5-one is a glass or resin ampoule, vial, syringe or bag. The injection according to claim 7, wherein the inner surface of the container is subjected to a silicoat treatment or a sulfur treatment. 9. The injection according to claim 7 or 8, wherein the space inside the container is replaced with an inert gas.