JPH07121861B2 - Stable injection containing 3-methyl-1-phenyl-2-pyrazolone-5-one - Google Patents
Stable injection containing 3-methyl-1-phenyl-2-pyrazolone-5-oneInfo
- Publication number
- JPH07121861B2 JPH07121861B2 JP28002286A JP28002286A JPH07121861B2 JP H07121861 B2 JPH07121861 B2 JP H07121861B2 JP 28002286 A JP28002286 A JP 28002286A JP 28002286 A JP28002286 A JP 28002286A JP H07121861 B2 JPH07121861 B2 JP H07121861B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrazolone
- methyl
- phenyl
- injection
- cysteine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は、下記構造式（１）で示される３−メチル−１
−フエニル−２−ピラゾロン−５−オンを主成分とする
注射剤に関し、更に詳しくは、長期安定な３−メチル−
１−フエニル−２−ピラゾロン−５−オンの溶液型注射
剤に関するものである。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to 3-methyl-1 represented by the following structural formula (1).
-Phenenyl-2-pyrazolone-5-one-based injections, more specifically, long-term stable 3-methyl-
The present invention relates to a solution-type injection of 1-phenyl-2-pyrazolone-5-one.
（従来の技術） ３−メチル−１−フエニル−２−ピラゾロン−５−オン
は、公知化合物であり、３−メチル−１−フエニル−２
−ピラゾロン又はノルアンチピリンとも呼ばれ、解熱鎮
痛剤であるアンチピリンの代謝物の一つとして知られて
いる。また医薬品、染料等の原料としても広く用いられ
ている化合物である。 (Prior Art) 3-Methyl-1-phenyl-2-pyrazolone-5-one is a known compound, and is 3-methyl-1-phenyl-2.
Also known as pyrazolone or norantipyrine, it is known as one of the metabolites of antipyrine, an antipyretic analgesic. It is also a compound widely used as a raw material for pharmaceuticals, dyes and the like.
最近、本化合物に脳血管障害の名種動物モデル実験で優
れた有効性が認められ、これまで有用な医薬品がなかつ
た脳卒中、脳腫瘍、頭部外傷の急性期にしばしば見られ
る脳虚血、脳浮腫等の脳血管障害時の治療薬として、そ
の臨床的応用がきわめて期待されている化合物である。Recently, this compound has been shown to be highly effective in experiments in animal models of cerebrovascular accidents, and for which no useful drug has been available so far, cerebral ischemia and cerebral ischemia often seen in the acute phase of stroke, brain tumor, and head injury. As a therapeutic drug for cerebrovascular disorders such as edema, it is a compound highly expected for its clinical application.
（発明が解決しようとする問題点） 本化合物は、固体状態では極めて安定であるが水溶液と
した場合には、溶存酸素により容易に酸化をうけ不溶性
異物を生成し、特にpH2.5以下、及びpH6.0以上で加速さ
れることが判明し液剤の製剤化にあたり相当な困難が予
想された。特に注射剤とする場合には不溶性異物の発生
は生体内に悪影響を及ぼし致命的欠陥となる。(Problems to be Solved by the Invention) This compound is extremely stable in the solid state, but when it is made into an aqueous solution, it easily oxidizes due to dissolved oxygen to produce an insoluble foreign matter, particularly at pH 2.5 or less, It was found to be accelerated at pH 6.0 and above, and considerable difficulties were expected in formulating liquid formulations. Especially when it is used as an injection, the generation of insoluble foreign matter adversely affects the inside of the body and causes a fatal defect.
（問題点を解決するための手段） 一般に、酸化による反応防止手段としては、抗酸化剤の
添加は有効な方法である。本化合物においても種々の抗
酸化剤のうち亜硫酸塩、亜硫酸水素塩及びピロ亜硫酸塩
から選ばれる１種以上を添加し、溶液のpHを2.5〜6.0に
することで安定性が増すことを見い出した。しかしなが
らその効果は充分でなく長期安定性を保証するには若干
の懸念があつた。そこでさらに鋭意検討を重ねた結果、
システイン類単独では何ら安定化効果が認められなかつ
たにもかかわらず、上記抗酸化剤とシステイン類を組み
合わせて添加することにより著しい安定化効果が認めら
れ、安定性の優れた注射剤が得られることを見い出し、
本発明を完成するに至つた。(Means for Solving Problems) In general, addition of an antioxidant is an effective method for preventing reaction by oxidation. It has been found that the stability of this compound is increased by adding at least one selected from sulfite, bisulfite and pyrosulfite among various antioxidants and adjusting the pH of the solution to 2.5 to 6.0. . However, the effect was not sufficient, and there was some concern about guaranteeing long-term stability. Therefore, as a result of further diligent examination,
Although no stabilizing effect was observed with cysteine alone, a remarkable stabilizing effect was observed by adding the above-mentioned antioxidant and cysteine in combination, and an injection with excellent stability was obtained. Find out
The present invention has been completed.
即ち、本発明の要旨は、亜硫酸塩、亜硫酸水素塩及びピ
ロ亜硫酸塩の中から選ばれる１種以上及びシステイン類
を含有する３−メチル−１−フエニル−２−ピラゾロン
−５−オンの水溶液であつて、かつ該溶液のpHが2.5〜
6.0の範囲にあることを特徴とする注射剤に存する。That is, the gist of the present invention is an aqueous solution of 3-methyl-1-phenyl-2-pyrazolone-5-one containing at least one selected from sulfite, bisulfite and pyrosulfite, and cysteine. And the pH of the solution is 2.5-
Injectables characterized by being in the range of 6.0.
本発明に用いる亜硫酸塩としては、亜硫酸ナトリウム
（Na2SO3）、亜硫酸カリウム（K2SO3）、亜硫酸カルシ
ウム（CaSO3）、亜硫酸水素塩としては、亜硫酸水素ナ
トリウム（NaHSO3）、亜硫酸水素カリウム（KHSO3）、
亜硫酸水素アンモニウム（NH4SO3）、ピロ亜硫酸塩とし
ては、ピロ亜硫酸ナトリウム（Na2S2O5）、ピロ亜硫酸
カリウム（K2S2O5）などが挙げられる。また、システイ
ン類としては、Ｌ−システイン、DL−システイン、Ｎ−
アセチルシステイン、およびそれらの塩酸塩等があげら
れる。上記抗酸化剤及びシステイン類の添加量は抗酸化
剤については、0.01〜5mg/ml（0.001〜0.5W/V％）、特
に0.1〜2mg/ml（0.01〜0.2W/V％）が好ましく、またシ
ステイン類については0.05〜5mg/ml（0.005〜0.5W/V
％）、特に0.1〜2mg/ml（0.01〜0.2W/V％）が好まし
い。安定化剤の添加量が上記範囲以下だと、安定化効果
が不充分となり、また、上記範囲以上だと安定化効果は
頭打ちとなり、かつ、安全性の面からも好ましくない。The sulfite used in the present invention includes sodium sulfite (Na 2 SO 3 ), potassium sulfite (K 2 SO 3 ), calcium sulfite (CaSO 3 ), and the bisulfite salt includes sodium hydrogen sulfite (NaHSO 3 ) and hydrogen sulfite. Potassium (KHSO 3 ),
Ammonium bisulfite (NH 4 SO 3), as the pyrosulfite, sodium metabisulfite (Na 2 S 2 O 5) , potassium metabisulfite (K 2 S 2 O 5), and the like. Moreover, as cysteine, L-cysteine, DL-cysteine, N-
Acetyl cysteine, and their hydrochlorides and the like. The amount of the antioxidant and cysteines added is about 0.01 to 5 mg / ml (0.001 to 0.5 W / V%), particularly 0.1 to 2 mg / ml (0.01 to 0.2 W / V%) for the antioxidant, For cysteine, 0.05 to 5 mg / ml (0.005 to 0.5 W / V
%), Especially 0.1 to 2 mg / ml (0.01 to 0.2 W / V%). If the amount of the stabilizer added is less than the above range, the stabilizing effect will be insufficient, and if it is more than the above range, the stabilizing effect will level off and it is not preferable from the viewpoint of safety.
本発明の注射剤は、液のpHが2.5〜6.0特にpH3.0〜4.0の
範囲で良好な安定化効果が得られる。このpHの調整には
一般に用いられている緩衝剤、pH調整剤が使用できる。
また酸素により悪影響を受ける他の化合物と同様、調製
に用いる水を予め脱気し、かつ分注後容器（例えばアン
プル、バイアルなど）内の空気を窒素ガスなどの不活性
ガスで置換することにより安定性は更に向上する。The injectable composition of the present invention has a good stabilizing effect when the pH of the solution is 2.5 to 6.0, particularly 3.0 to 4.0. For adjusting the pH, commonly used buffers and pH adjusters can be used.
Also, as with other compounds that are adversely affected by oxygen, the water used for the preparation is degassed in advance, and after dispensing, the air in the container (eg ampoule, vial) is replaced with an inert gas such as nitrogen gas Stability is further improved.
本化合物の注射剤は、必要に応じて薬学上許容される溶
剤、溶解補助剤、等張化剤、緩衝剤、保存剤等を用いて
調製することができる。The injectable preparation of the present compound can be prepared by using a pharmaceutically acceptable solvent, solubilizing agent, isotonicity agent, buffer, preservative and the like as necessary.
（実施例） 以下実施例及び試験例により本発明を更に詳細に説明す
るが、本発明は、その要旨を越えない限り、以下の実施
例によつて何ら限定されるものではない。(Examples) Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited to the following Examples without departing from the gist thereof.
実施例１ 脱気した注射用蒸留水900mlにピロ亜硫酸ナトリウム1g
及びＬ−システイン塩酸塩0.5gを添加溶解する。次に本
化合物2gを添加溶解した後、水酸化ナトリウム溶液を滴
下してpH3.5に調整し、注射用蒸留水を加えて全量1,000
mlとする。この溶液を無菌過後、5ml用のアンプルに
充填し、容器内の空気を窒素で置換した後熔封して注射
剤を得た。Example 1 1 g of sodium pyrosulfite was added to 900 ml of degassed distilled water for injection.
And 0.5 g of L-cysteine hydrochloride are added and dissolved. Next, 2 g of this compound was added and dissolved, and then sodium hydroxide solution was added dropwise to adjust the pH to 3.5, and distilled water for injection was added to a total amount of 1,000.
ml. After the solution was aseptically filled, an ampoule for 5 ml was filled, the air in the container was replaced with nitrogen, and then the container was sealed to obtain an injection.
実施例２ 実施例１のピロ亜硫酸ナトリウム1gに代えて亜硫酸水素
ナトリウム1gを用い実施例１と同様の方法で注射剤を得
た。Example 2 An injection was obtained in the same manner as in Example 1, except that 1 g of sodium hydrogen sulfite was used instead of 1 g of sodium pyrosulfite.
比較例１ 実施例１のピロ亜硫酸ナトリウム及びＬ−システイン塩
酸塩を用いることなく、また、pH調整剤として水酸化ナ
トリウム溶液に代えて、塩酸溶液を用い、他は実施例１
と同様の方法でpHを3.5に調製し注射剤を得た。Comparative Example 1 Without using sodium pyrosulfite and L-cysteine hydrochloride of Example 1, a hydrochloric acid solution was used instead of the sodium hydroxide solution as a pH adjuster, and the other examples were used.
The pH was adjusted to 3.5 by the same method as described above to obtain an injection.
比較例２ 実施例１のＬ−システイン塩酸塩を用いることなく、ま
た水酸化ナトリウム溶液に代えて塩酸溶液でpHを3.5に
調製し、他は実施例１と同様の方法で注射剤を得た。Comparative Example 2 An injection was obtained by the same method as in Example 1 except that the L-cysteine hydrochloride of Example 1 was not used, and that the pH was adjusted to 3.5 with a hydrochloric acid solution instead of the sodium hydroxide solution. .
比較例３ 実施例１においてpHを調整せずに他は実施例１と同様の
方法で注射剤を得た。Comparative Example 3 An injection was obtained in the same manner as in Example 1 except that pH was not adjusted in Example 1.
試験例 実施例１〜２及び比較例１〜３で得られた注射剤を60℃
の恒温槽に保存し、経時的に不溶性異物の発生の有無を
観察した。その結果は下記表に示すとおりであり、本発
明の注射剤は安定性に優れていることが認められた。Test Example The injections obtained in Examples 1-2 and Comparative Examples 1-3 were treated at 60 ° C.
The sample was stored in a constant temperature bath, and the presence or absence of insoluble foreign matter was observed over time. The results are shown in the table below, and it was confirmed that the injection of the present invention had excellent stability.
（発明の効果） 本発明の注射剤は、長期間その安定性に優れ、不溶性異
物が発生することがない。 (Effects of the Invention) The injectable composition of the present invention has excellent stability for a long period of time and does not generate insoluble foreign matter.
Claims (1)
塩から選ばれる１種以上及びシステイン類を含有する３
−メチル−１−フェニル−２−ピラゾロン−５−オンの
水溶液であって、かつ該溶液のpHが2.5〜6.0の範囲にあ
ることを特徴とする注射剤。1. A compound containing at least one selected from sulfite, bisulfite and pyrosulfite, and cysteines.
An injectable solution, which is an aqueous solution of methyl-1-phenyl-2-pyrazolone-5-one and has a pH in the range of 2.5 to 6.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28002286A JPH07121861B2 (en) | 1986-11-25 | 1986-11-25 | Stable injection containing 3-methyl-1-phenyl-2-pyrazolone-5-one |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28002286A JPH07121861B2 (en) | 1986-11-25 | 1986-11-25 | Stable injection containing 3-methyl-1-phenyl-2-pyrazolone-5-one |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63132833A JPS63132833A (en) | 1988-06-04 |
| JPH07121861B2 true JPH07121861B2 (en) | 1995-12-25 |
Family
ID=17619207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28002286A Expired - Lifetime JPH07121861B2 (en) | 1986-11-25 | 1986-11-25 | Stable injection containing 3-methyl-1-phenyl-2-pyrazolone-5-one |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07121861B2 (en) |
Cited By (3)
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|---|---|---|---|---|
| JP2006257020A (en) * | 2005-03-17 | 2006-09-28 | Towa Yakuhin Kk | Stable high-concentration edaravone injection |
| WO2019031495A1 (en) | 2017-08-08 | 2019-02-14 | 田中 正彦 | Drug containing pyrazolone derivative |
| WO2020091036A1 (en) | 2018-11-02 | 2020-05-07 | 田辺三菱製薬株式会社 | Edaravone suspension for oral administration |
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| JP5255313B2 (en) * | 2008-04-01 | 2013-08-07 | キョーリンリメディオ株式会社 | Stable edaravone injection |
| EP2754440B1 (en) | 2011-09-05 | 2019-04-03 | Mitsubishi Tanabe Pharma Corporation | Medicinal agent for treating amyotrophic lateral sclerosis or preventing progression of phase of amyotrophic lateral sclerosis |
| CN103751104A (en) * | 2014-01-23 | 2014-04-30 | 扬子江药业集团南京海陵药业有限公司 | Edaravone injection and preparation method thereof |
| EP3593807B1 (en) * | 2017-03-07 | 2023-09-06 | Mochida Pharmaceutical Co., Ltd. | Alginate liquid formulation |
| WO2019070932A1 (en) | 2017-10-04 | 2019-04-11 | Mitsubishi Tanabe Pharma Corporation | Method for treating amyotrophic lateral sclerosis and method for suppressing progress of amyotrophic lateral sclerosis |
| WO2019070308A1 (en) | 2017-10-04 | 2019-04-11 | Mitsubishi Tanabe Pharma Corporation | Method for treating amyotrophic lateral sclerosis and method for suppressing progress of amyotrophic lateral sclerosis |
| MX2020003578A (en) * | 2017-10-13 | 2020-07-22 | Treeway Tw001 B V | Edaravone salt. |
| WO2019167178A1 (en) * | 2018-02-28 | 2019-09-06 | 田辺三菱製薬株式会社 | Analysis method of 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug, treatment for amyotrophic lateral sclerosis, inhibition of progression of amyotrophic lateral sclerosis, and method of producing drug containing 3-methyl-1-phenyl-2-pyrazolin-5-one bulk drug |
-
1986
- 1986-11-25 JP JP28002286A patent/JPH07121861B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006257020A (en) * | 2005-03-17 | 2006-09-28 | Towa Yakuhin Kk | Stable high-concentration edaravone injection |
| WO2019031495A1 (en) | 2017-08-08 | 2019-02-14 | 田中 正彦 | Drug containing pyrazolone derivative |
| WO2020091036A1 (en) | 2018-11-02 | 2020-05-07 | 田辺三菱製薬株式会社 | Edaravone suspension for oral administration |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63132833A (en) | 1988-06-04 |
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