JP4296374B2 - Stable liquid formulation - Google Patents
Stable liquid formulation Download PDFInfo
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- JP4296374B2 JP4296374B2 JP2001371826A JP2001371826A JP4296374B2 JP 4296374 B2 JP4296374 B2 JP 4296374B2 JP 2001371826 A JP2001371826 A JP 2001371826A JP 2001371826 A JP2001371826 A JP 2001371826A JP 4296374 B2 JP4296374 B2 JP 4296374B2
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- JP
- Japan
- Prior art keywords
- liquid preparation
- acid
- propylene glycol
- mesylate
- polyethylene glycol
- 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
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Description
【０００１】
【発明の属する技術分野】
本発明は、膵炎治療剤等として用いられているメシル酸ナファモスタットまたはメシル酸ガベキサートを有効成分として含有する液剤に関する。さらに詳しくは、メシル酸ナファモスタットまたはメシル酸ガベキサートをアミノ酸とともに非水溶剤に溶解してなる、安定化された液製剤に関する。
【０００２】
【従来の技術】
本発明の有効成分であるメシル酸ナファモスタットおよびメシル酸ガベキサートは、ともに注射剤として膵炎等の治療に用いられているが、水中で加水分解されやすいことが知られている。このため、これらの医薬品は従来より凍結乾燥製剤として供給され、用時、溶解液に溶かして患者に投与されており、安定な液状製剤が求められていたものである。
【０００３】
そこで、これらの医薬品を液剤として供給するべく、「抗膵炎用薬物をエタノールとプロピレングリコール及び／又はポリエチレングリコールの混合液に溶解する注射剤」（特開平5-246891号公報）、「プロピレングリコール及び酸を含む混合液中に主剤としてメシル酸ナファモスタットを溶解した液剤」（特開2001-106629号公報）、「抗膵炎用薬物をエタノールとプロピレングリコール及び／又はポリエチレングリコールの混合液に溶解する液剤」（特開2001-163776号公報）ような研究が行われてきている。
【０００４】
【発明が解決しようとする課題】
しかしながら、上述した液剤では安定性の面で満足できるものではなく、より安定な液状製剤が求められている。
【０００５】
【課題を解決するための手段】
本件発明者は、より安定な液状製剤を開発すべく鋭意研究した結果、メシル酸ナファモスタットまたはメシル酸ガベキサートを含有する液状製剤において、非水溶剤に溶解するとともにアミノ酸を共存させることによって、意外にも分解・沈殿が抑制され、安定化された液状製剤を得られることを知見したものである。すなわち、
（１）メシル酸ナファモスタットまたはメシル酸ガベキサートを含有する液状製剤において、非水溶剤に溶解するとともにアミノ酸を共存させることを特徴とする安定化された液状製剤。
（２）アミノ酸として、グリシンおよび／またはその塩を用いることを特徴とする（１）項に記載の液状製剤。
（３）アミノ酸として、グルタミン酸および／またはその塩を用いることを特徴とする（１）項に記載の液状製剤。
（４）アミノ酸として、アルギニンおよび／またはその塩を用いることを特徴とする（１）項に記載の液状製剤。
（５）アミノ酸として、ヒスチジンおよび／またはその塩を用いることを特徴とする（１）項に記載の液状製剤。
（６）非水溶剤として、プロピレングリコール、ポリエチレングリコールおよびグリセリンからなる群から選択される１以上を用いることを特徴とする（１）項に記載の液状製剤。
（７）非水溶剤が、プロピレングリコールおよびポリエチレングリコールの混合溶剤であることを特徴とする（６）項に記載の液状製剤。
（８）さらに酸を含有することを特徴とする（１）項に記載の液状製剤。
（９）酸として塩酸を用いることを特徴とする（８）項に記載の液状製剤。
（１０）酸としてコハク酸を用いることを特徴とする（８）項に記載の液状製剤。
を提供するものである。
【０００６】
【発明の実施の形態】
本発明の液状製剤は、メシル酸ナファモスタットまたはメシル酸ガベキサートを含有する非水溶液製剤において、アミノ酸を共存させることを特徴とする液状製剤である。
【０００７】
この発明で使用されるアミノ酸としては、グリシン，アラニン，システイン，シスチン，メチオニン，アスパラギン酸，グルタミン酸ナトリウム，グルタミン酸−リジン，アルギニン及び塩酸ヒスチジン等などが挙げられ、中でもグリシンの使用が特に好ましい。これらのアミノ酸は単独で使用しても、また、２種以上を組み合わせて使用してもよい。
【０００８】
また、本発明で使用される非水溶剤としては、プロピレングリコール、ポリエチレングリコールおよびグリセリン等が挙げられ、これらの溶剤は単独で使用しても、２以上を組み合わせて使用してもよい。これらの２以上の組合せとして、プロピレングリコールおよびポリエチレングリコールの組合せによる混合溶剤であることが特に好ましい。混合して用いる場合には、プロピレングリコール：ポリエチレングリコール（容量比）＝１：１〜２００：１の混合溶媒として用いることが好ましい。これらの非水溶剤は、実質的に水を含まないことが好ましく、例えば日本薬局方で規定される０．５％以下の水分含量であることが好ましく、さらに水分含量を減じたプロピレングリコール、ポリエチレングリコールおよびグリセリンであることが好ましい。
【０００９】
本発明で使用する酸としては、通常医薬品に用いられるものとしては、塩酸、酢酸、乳酸、硫酸、燐酸、コハク酸、クエン酸、リンゴ酸、、グルコン酸、酒石酸、ニコチン酸、マレイン酸、安息香酸等の酸を挙げることができる。これらの酸は単独で使用してもよく、２種以上を組み合わせて使用することもできる。これらの酸のうち、特に塩酸を用いることが特に好ましい。
【００１０】
本発明の液状製剤の製造は、通常の注射剤を製造する方法でよく、例えば、非水溶剤に薬剤を加えて攪拌・混合し、アミノ酸を加えてさらに混合し、さらに酸を加えて混合して溶解させることなどにより製造することができる。
【００１１】
実施例１ プロピレングリコール１００ｍｌに希塩酸０．３mｌ及びグリシン２８０ｍｇを加え，約１００℃で撹拌溶解し、これにメシル酸ナファモスタット５ｇを加えて溶解した。この溶液を０．２μｍのメンブレンフィルターでろ過し、ろ液を１ｍｌずつサルファー処理済みの褐色ガラスアンプル中に分注し、アンプル内を窒素置換したのち溶封して、液状製剤を得た。
【００１２】
実施例１における本発明の液状製剤は、６０℃、１週間における保存試験の結果、液体クロマトグラフィーによる測定の結果、分解物含量が０．３８％であった。このように本発明の液状製剤は、高温保存によってもメシル酸ナファモスタットの分解が少なく、安定であった。
【００１３】
比較例１ グリシンを含有させない他は実施例１と同様に操作し、液状製剤（比較例１）を得た。上記と同様の測定の結果、分解物含量が８．７６％であった。
【００１４】
実施例２ メシル酸ナファモスタット５ｇをプロピレングリコール１００ｍＬに加えて撹拌し、これにグルタミン酸ナトリウム３００ｍｇ、希塩酸０．３ｍＬおよびポリエチレングリコール３０ｍＬを添加した。この溶液を０．２μｍのメンブレンフィルターでろ過し、ろ液を２．６ｍＬずつサルファー処理済みの褐色ガラスアンプル中に分注し、アンプル内を窒素置換したのち溶封して、液状製剤を得た。
【００１５】
実施例３ メシル酸ナファモスタット５ｇをプロピレングリコール１００ｍＬに加えて撹拌し、これに塩酸ヒスチジン２００ｍｇ、コハク酸５００ｍｇおよびポリエチレングリコール３０ｍＬを添加した。この溶液を０．２μｍのメンブレンフィルターでろ過し、ろ液を２．６ｍＬずつサルファー処理済みの褐色ガラスアンプル中に分注し、アンプル内を窒素置換したのち溶封して、液状製剤を得た。
【００１６】
【発明の効果】
本発明の液状製剤は、メシル酸ナファモスタットまたはメシル酸ガベキサートをアミノ酸とともに、非水溶剤に溶解してなる液状製剤であり、長期保存に置いても安定な液剤である。液状製剤であるため、凍結乾燥製剤とする工程が不要であり、また、用時の溶解操作が不要である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a liquid preparation containing nafamostat mesylate or gabexate mesylate as an active ingredient, which is used as a therapeutic agent for pancreatitis and the like. More specifically, the present invention relates to a stabilized liquid preparation obtained by dissolving nafamostat mesylate or gabexate mesylate together with an amino acid in a non-aqueous solvent.
[0002]
[Prior art]
Both nafamostat mesylate and gabexate mesylate, which are the active ingredients of the present invention, are used as injections for the treatment of pancreatitis and the like, but are known to be easily hydrolyzed in water. For this reason, these pharmaceuticals have been conventionally supplied as lyophilized preparations, dissolved in a solution at the time of use and administered to patients, and stable liquid preparations have been desired.
[0003]
Therefore, in order to supply these pharmaceuticals as solutions, “injections for dissolving anti-pancreatitis drugs in a mixture of ethanol and propylene glycol and / or polyethylene glycol” (Japanese Patent Laid-Open No. 5-246891), “propylene glycol and "Liquid preparation in which nafamostat mesylate is dissolved as a main ingredient in a mixed liquid containing acid" (Japanese Patent Laid-Open No. 2001-106629), "Liquid preparation for dissolving anti-pancreatitis drug in mixed liquid of ethanol and propylene glycol and / or polyethylene glycol""(JP 2001-163776 A)" has been studied.
[0004]
[Problems to be solved by the invention]
However, the above-mentioned liquid preparation is not satisfactory in terms of stability, and a more stable liquid preparation is required.
[0005]
[Means for Solving the Problems]
As a result of diligent research to develop a more stable liquid preparation, the present inventors have surprisingly found that a liquid preparation containing nafamostat mesylate or gabexate mesylate is dissolved in a nonaqueous solvent and coexists with an amino acid. It has also been found that a stable liquid preparation can be obtained in which decomposition and precipitation are suppressed. That is,
(1) A stabilized liquid preparation containing nafamostat mesylate or gabexate mesylate, which dissolves in a non-aqueous solvent and coexists with an amino acid.
(2) The liquid preparation according to item (1), wherein glycine and / or a salt thereof is used as an amino acid.
(3) The liquid preparation according to (1), wherein glutamic acid and / or a salt thereof is used as the amino acid.
(4) The liquid preparation according to item (1), wherein arginine and / or a salt thereof is used as an amino acid.
(5) The liquid preparation according to item (1), wherein histidine and / or a salt thereof is used as an amino acid.
(6) The liquid preparation according to item (1), wherein one or more selected from the group consisting of propylene glycol, polyethylene glycol and glycerin is used as the non-aqueous solvent.
(7) The liquid preparation according to item (6), wherein the non-aqueous solvent is a mixed solvent of propylene glycol and polyethylene glycol.
(8) The liquid preparation according to item (1), further comprising an acid.
(9) The liquid preparation according to item (8), wherein hydrochloric acid is used as the acid.
(10) The liquid preparation according to (8), wherein succinic acid is used as the acid.
Is to provide.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The liquid preparation of the present invention is a liquid preparation characterized in that an amino acid is allowed to coexist in a non-aqueous solution preparation containing nafamostat mesylate or gabexate mesylate.
[0007]
Examples of amino acids used in the present invention include glycine, alanine, cysteine, cystine, methionine, aspartic acid, sodium glutamate, glutamic acid-lysine, arginine, histidine hydrochloride and the like, and glycine is particularly preferable. These amino acids may be used alone or in combination of two or more.
[0008]
In addition, examples of the non-aqueous solvent used in the present invention include propylene glycol, polyethylene glycol and glycerin. These solvents may be used alone or in combination of two or more. A combination solvent of propylene glycol and polyethylene glycol is particularly preferable as a combination of two or more of these. When mixed and used, it is preferably used as a mixed solvent of propylene glycol: polyethylene glycol (volume ratio) = 1: 1 to 200: 1. These non-aqueous solvents are preferably substantially free of water, for example, preferably have a water content of 0.5% or less as defined by the Japanese Pharmacopoeia, and further have propylene glycol and polyethylene with a reduced water content. Glycol and glycerin are preferred.
[0009]
As acids used in the present invention, those usually used in pharmaceuticals are hydrochloric acid, acetic acid, lactic acid, sulfuric acid, phosphoric acid, succinic acid, citric acid, malic acid, gluconic acid, tartaric acid, nicotinic acid, maleic acid, benzoic acid. Acids such as acids can be mentioned. These acids may be used alone or in combination of two or more. Of these acids, it is particularly preferable to use hydrochloric acid.
[0010]
The liquid preparation of the present invention may be produced by a method for producing an ordinary injection. For example, a drug is added to a non-aqueous solvent and stirred and mixed, an amino acid is added and further mixed, and an acid is further added and mixed. It can be manufactured by dissolving.
[0011]
Example 1 To 100 ml of propylene glycol, 0.3 ml of dilute hydrochloric acid and 280 mg of glycine were added and dissolved by stirring at about 100 ° C., and 5 g of nafamostat mesylate was added and dissolved. This solution was filtered through a 0.2 μm membrane filter, and 1 ml of the filtrate was dispensed into a sulfur-treated brown glass ampule, and the ampule was purged with nitrogen and sealed to obtain a liquid preparation.
[0012]
The liquid preparation of the present invention in Example 1 had a degradation product content of 0.38% as a result of a storage test at 60 ° C. for one week and a measurement by liquid chromatography. Thus, the liquid preparation of the present invention was stable with little degradation of nafamostat mesylate even after storage at high temperature.
[0013]
Comparative Example 1 A liquid preparation (Comparative Example 1) was obtained in the same manner as in Example 1 except that glycine was not contained. As a result of the same measurement as described above, the decomposition product content was 8.76%.
[0014]
Example 2 5 g of nafamostat mesylate was added to 100 mL of propylene glycol and stirred, and 300 mg of sodium glutamate, 0.3 mL of dilute hydrochloric acid and 30 mL of polyethylene glycol were added thereto. This solution was filtered through a 0.2 μm membrane filter, and the filtrate was dispensed in 2.6 mL portions into a sulfur-treated brown glass ampule, and the ampule was purged with nitrogen and sealed to obtain a liquid preparation. .
[0015]
Example 3 5 g of nafamostat mesylate was added to 100 mL of propylene glycol and stirred, and 200 mg of histidine hydrochloride, 500 mg of succinic acid, and 30 mL of polyethylene glycol were added thereto. This solution was filtered through a 0.2 μm membrane filter, and the filtrate was dispensed in 2.6 mL portions into a sulfur-treated brown glass ampule, and the ampule was purged with nitrogen and sealed to obtain a liquid preparation. .
[0016]
【The invention's effect】
The liquid preparation of the present invention is a liquid preparation prepared by dissolving nafamostat mesylate or gabexate mesylate together with an amino acid in a non-aqueous solvent, and is a stable liquid preparation even after long-term storage. Since it is a liquid preparation, a step for preparing a freeze-dried preparation is not required, and a dissolution operation at the time of use is not required.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001371826A JP4296374B2 (en) | 2001-12-05 | 2001-12-05 | Stable liquid formulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001371826A JP4296374B2 (en) | 2001-12-05 | 2001-12-05 | Stable liquid formulation |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009004762A Division JP2009102381A (en) | 2009-01-13 | 2009-01-13 | Stabilized liquid preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2003171273A JP2003171273A (en) | 2003-06-17 |
| JP4296374B2 true JP4296374B2 (en) | 2009-07-15 |
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ID=19180819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001371826A Expired - Lifetime JP4296374B2 (en) | 2001-12-05 | 2001-12-05 | Stable liquid formulation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4296374B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526017B (en) * | 2011-12-21 | 2014-08-27 | 湖北德康药业有限公司 | Gabexate mesilate pharmaceutical composition and preparation method of freeze-dried powder injection thereof |
| JP6293471B2 (en) * | 2013-12-12 | 2018-03-14 | アシザワ・ファインテック株式会社 | Horizontal dry crusher |
| CN105412060B (en) * | 2015-11-15 | 2018-06-08 | 北京泰德制药股份有限公司 | A kind of Nafamostat Mesilate composition and preparation method thereof |
-
2001
- 2001-12-05 JP JP2001371826A patent/JP4296374B2/en not_active Expired - Lifetime
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| Publication number | Publication date |
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| JP2003171273A (en) | 2003-06-17 |
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