JP2844351B2 - Aqueous solution of stable polymyxin antibiotics - Google Patents
Aqueous solution of stable polymyxin antibioticsInfo
- Publication number
- JP2844351B2 JP2844351B2 JP1181168A JP18116889A JP2844351B2 JP 2844351 B2 JP2844351 B2 JP 2844351B2 JP 1181168 A JP1181168 A JP 1181168A JP 18116889 A JP18116889 A JP 18116889A JP 2844351 B2 JP2844351 B2 JP 2844351B2
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- Prior art keywords
- acid
- polymyxin
- aqueous solution
- sulfate
- titer
- Prior art date
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、注射剤として有用な、安定なポリミキシン
抗生物質の医薬用水性溶液剤に関する。The present invention relates to a stable pharmaceutical aqueous solution of a polymyxin antibiotic, which is useful as an injection.
［従来の技術及びその課題］ ポリミキシン系抗生物質は、バチルス・ポリミキサ
（Bacillus polymyxa）またはその近縁菌の生産する塩
基性アシル化ペプチドの総称であり、構成アミノ酸とし
て分子内にジアミノ酪酸（DAB）を数モル含み、緑膿
菌、赤痢菌、大腸菌、肺炎桿菌等のグラム陰性菌に対
し、強い抗菌力を有するものである。ポリミキシン系抗
生物質の例としては、ポリミキシンA1、A2、B1、B2、
D1、D2、M1、M2、P1、P2、AK、コリスチンＡ、Ｂ、サー
キュリンＡ、Ｂ、ポリペプチン、EM−49等が挙げられ
（「別冊蛋白質核酸酵素微生物のつくる生理活性ペプチ
ド」，第114〜130ページ，共立出版,1976年５月発
行）、このうちポリミキシンＢやコリスチンは抗菌剤と
して医薬に用いられている。[Prior art and its problems] Polymyxin antibiotics are a general term for basic acylated peptides produced by Bacillus polymyxa or its closely related bacteria, and have diaminobutyric acid (DAB) in the molecule as a constituent amino acid. And has strong antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa, Shigella, Escherichia coli, Klebsiella pneumoniae and the like. Examples of polymyxin antibiotics include polymyxins A 1 , A 2 , B 1 , B 2 ,
D 1 , D 2 , M 1 , M 2 , P 1 , P 2 , AK, colistin A, B, circulin A, B, polypeptin, EM-49 and the like. Bioactive Peptides ", pp. 114-130, Kyoritsu Shuppan, published May 1976), of which polymyxin B and colistin are used in medicine as antibacterial agents.
しかしながら、ポリミキシン系抗生物質は水溶液状態
では比較的不安定であり、長期間にわたり力価を維持す
ることは困難である。このため、例えば従来市販されて
いる硫酸ポリミキシンＢの注射剤は用時溶解の剤型で供
給されている。しかし、ポリミキシン系抗生物質は溶解
に時間がかかるだけでなく、溶解の際溶液を強く振盪す
ると発泡してしまい、しかもこれが容易に消失しないと
いう欠点を有している。However, polymyxin antibiotics are relatively unstable in aqueous solution, and it is difficult to maintain the titer for a long period of time. For this reason, for example, conventionally commercially available injections of polymyxin B sulfate are supplied in the form of dissolution before use. However, polymyxin antibiotics have the disadvantage that not only takes a long time to dissolve, but also foams when the solution is shaken vigorously during the dissolution, and that it does not disappear easily.
このため、ポリミキシン系抗生物質の安定な水性溶液
製剤の提供が要望されている。Therefore, there is a need to provide a stable aqueous solution preparation of a polymyxin antibiotic.
［課題を解決するための手段］ かかる実情において、本発明者らはポリミキシン系抗
生物質注射液を安定化し得る添加剤を鋭意研究した結
果、特定のアミノ酸、糖類、カルボン酸または高分子化
合物がポリミキシン系抗生物質の優れた安定化剤となる
ことを見出し、本発明を完成した。[Means for Solving the Problems] Under such circumstances, the present inventors have conducted intensive studies on additives capable of stabilizing a polymyxin antibiotic injection solution, and as a result, a specific amino acid, saccharide, carboxylic acid or polymer compound was found to be polymyxin. The present inventors have found that they are excellent stabilizers for antibiotics, and have completed the present invention.
すなわち、本発明は、ポリミキシン系抗生物質の水溶
性塩を含有する水性溶液に、水酸基を有するアミノ酸、
酸性アミノ酸、還元性六炭糖類（但し、ブドウ糖を除
く）、脂肪族又は芳香族炭化水素にカルボキシル基のみ
が置換したもの、脂肪族炭化水素にカルボキシル基と水
酸基のみが置換したもの、及び水溶性高分子（但し、シ
クロデキストリンを除く）からなる群より選ばれる１種
または２種以上を配合したことを特徴とするポリミキシ
ン系抗生物質の安定な医薬用水性溶液剤を提供するもの
である。That is, the present invention provides an aqueous solution containing a water-soluble salt of a polymyxin antibiotic, an amino acid having a hydroxyl group,
Acidic amino acids, reducing hexoses (excluding glucose), aliphatic or aromatic hydrocarbons substituted only with carboxyl groups, aliphatic hydrocarbons substituted only with carboxyl groups and hydroxyl groups, and water-soluble An object of the present invention is to provide a stable aqueous pharmaceutical solution of a polymyxin antibiotic, which comprises one or more selected from the group consisting of polymers (excluding cyclodextrins).
本発明に用いるポリミキシン系抗生物質は、無機酸ま
たは有機酸の水溶性塩として用いられる。無機酸及び有
機酸としては特に限定されず、例えば無機酸として塩
酸、硫酸、リン酸、硝酸、ホウ酸等が、有機酸としてギ
酸、酢酸、プロピオン酸、安息香酸、シュウ酸、マロン
酸、コハク酸、グルタル酸、アジピン酸、フタル酸、グ
リコール酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタ
ンスルホン酸等が用いられる。The polymyxin antibiotic used in the present invention is used as a water-soluble salt of an inorganic acid or an organic acid. The inorganic acid and the organic acid are not particularly limited. For example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, boric acid and the like as inorganic acids, and formic acid, acetic acid, propionic acid, benzoic acid, oxalic acid, malonic acid, and succinic acid as organic acids. Acids, glutaric acid, adipic acid, phthalic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and the like are used.
また、本発明に適用可能な水性溶液としては、例えば
水溶液、生理食塩液、アルコール含有水溶液等が挙げら
れる。Further, examples of the aqueous solution applicable to the present invention include an aqueous solution, a physiological saline solution, an alcohol-containing aqueous solution, and the like.
本発明において用いられる添加剤（安定化剤）のう
ち、水酸基を有するアミノ酸としては例えばセリン、ト
レオニン、ヒドロキシプロリン等が、酸性アミノ酸とし
ては例えばグルタミン酸、アスパラギン酸等が、還元性
六炭糖としては例えばマンノース、ガラクトース、フラ
クトース等が、脂肪族又は芳香族炭化水素にカルボキシ
ル基のみが置換したものとしては例えばギ酸、酢酸、プ
ロピオン酸、酪酸、シュウ酸、マロン酸、コハク酸、グ
ルタル酸、アジピン酸、フタル酸等が、脂肪族炭化水素
にカルボキシル基と水酸基のみが置換したものとしては
例えばグリコール酸、乳酸、リンゴ酸、酒石酸、クエン
酸等が、水溶性高分子としては例えばメチルセルロー
ス、ヒドロキシプロピルセルロース、ヒドロキシプロピ
ルメチルセルロース、カルボキシメチルセルロースナト
リウム、プルラン、アラビアゴム、ゼラチン、ポリビニ
ルピロリドン、ポリビニルアルコール、ポリエチレング
リコール、ポリオキシエチレン硬化ヒマシ油等が挙げら
れる。これらは単独で、または２種以上組み合わせて使
用できる。Among the additives (stabilizers) used in the present invention, amino acids having a hydroxyl group include, for example, serine, threonine, and hydroxyproline; acidic amino acids include, for example, glutamic acid and aspartic acid; For example, mannose, galactose, fructose, and the like, as those in which only a carboxyl group is substituted with an aliphatic or aromatic hydrocarbon, for example, formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid For example, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, and the like as those in which only a carboxyl group and a hydroxyl group are substituted for an aliphatic hydrocarbon, such as phthalic acid, and the like, and water-soluble polymers such as methyl cellulose, hydroxypropyl cellulose , Hydroxypropyl methylcellulose, mosquito Bo sodium carboxymethylcellulose, pullulan, gum arabic, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, polyoxyethylene hydrogenated castor oil, and the like. These can be used alone or in combination of two or more.
これらの安定化剤の使用量は、ポリミキシン系抗生物
質100mg力価当たり1mg以上、特に10mg以上が好ましい。The amount of these stabilizers to be used is preferably 1 mg or more, particularly preferably 10 mg or more per 100 mg titer of the polymyxin antibiotic.
［実施例］ 以下、実施例を挙げて更に詳細に説明するが、本発明
はこれらに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, but the present invention is not limited thereto.
なお、実施例中のポリミキシン系抗生物質の力価は、
エシェリヒア・コリNIHJ（Escherichia coli NIHJ）を
検定菌として、日本抗生物質医薬品基準に基づいて測定
した。The titer of the polymyxin antibiotic in the Examples is
Escherichia coli NIHJ (Escherichia coli NIHJ) was used as a test bacterium, and the measurement was carried out based on Japanese Antibiotic Drug Standards.
実施例１ 硫酸ポリミキシンＢ（8600U/mg）698mgにグルタミン
酸０〜0.4w/v％を含む注射用蒸留水に溶解し、全量を12
0mlに調整した。この液を無菌ろ過し、40℃、RH75％の
恒温恒湿器に保存し、１ヵ月後及び２ヵ月後の硫酸ポリ
ミキシンＢの力価を測定し、初期力価に対する残存率を
求めた。Example 1 Polymyxin B sulfate (8600 U / mg) was dissolved in 698 mg of glutamic acid in distilled water for injection containing 0 to 0.4 w / v%.
Adjusted to 0 ml. This solution was aseptically filtered, stored in a thermo-hygrostat at 40 ° C. and 75% RH, and the titer of polymyxin B sulfate after 1 month and 2 months was measured to determine the residual ratio to the initial titer.
この結果を第１表に示す。 Table 1 shows the results.
実施例２ 硫酸ポリミキシンＢ（8600U/mg）6.977gにＬ−アスパ
ラギン酸2.4gを加え、注射用蒸留水に溶解して全量を12
00mlに調整した。この液を無菌ろ過し、35ml容量のバイ
アル瓶に10mlずつ充填、密封し、40℃、RH75％の恒温恒
湿器に保存し、１ヵ月後及び２ヵ月後の硫酸ポリミキシ
ンＢの力価を測定し、初期力価に対する残存率を求め
た。 Example 2 2.4 g of L-aspartic acid was added to 6.977 g of polymyxin sulfate B (8600 U / mg) and dissolved in distilled water for injection to give a total amount of 12 g.
Adjusted to 00ml. This solution was aseptically filtered, filled into vials of 35 ml capacity in 10 ml portions, sealed, and stored in a thermo-hygrostat at 40 ° C. and 75% RH, and the titer of polymyxin B sulfate after 1 month and 2 months was measured. Then, the residual ratio with respect to the initial titer was determined.
また、Ｌ−アスパラギン酸の代わりにＬ−セリン、Ｌ
−トレオニン、Ｌ−ヒドロキシプロリン、Ｄ−アスパラ
ギン酸またはＬ−グルタミン酸を用いた場合、並びに対
照として無添加の場合及びグリシン、バリン、Ｌ−ロイ
シン、Ｌ−プロリン、Ｌ−アスパラギン酸ナトリウムま
たはＬ−グルタミン酸ナトリウムを用いた場合について
も同様に残存率を求めた。Also, instead of L-aspartic acid, L-serine, L-serine,
-When threonine, L-hydroxyproline, D-aspartic acid or L-glutamic acid was used, and in the absence of control and glycine, valine, L-leucine, L-proline, sodium L-aspartate or L-glutamic acid In the case where sodium was used, the residual ratio was similarly obtained.
この結果を第２表に示す。 The results are shown in Table 2.
実施例３ 硫酸ポリミキシンＢ（8600U/mg）6.977gにＤ−マンノ
ース12.0gを加え、注射用蒸留水に溶解して全量を1200m
lに調整した。この液を無菌ろ過し、35ml容量のバイア
ル瓶に10mlずつ充填、密封し、40℃、RH75％の恒温恒湿
器に保存し、１ヵ月後及び２ヵ月後の硫酸ポリミキシン
Ｂの力価を測定し、初期力価に対する残存率を求めた。 Example 3 12.0 g of D-mannose was added to 6.977 g of polymyxin B sulfate (8600 U / mg) and dissolved in distilled water for injection to make a total amount of 1200 m.
Adjusted to l. This solution was aseptically filtered, filled into vials of 35 ml capacity in 10 ml portions, sealed, and stored in a thermo-hygrostat at 40 ° C. and 75% RH, and the titer of polymyxin B sulfate after 1 month and 2 months was measured. Then, the residual ratio with respect to the initial titer was determined.
また、Ｄ−マンノースの代わりにＤ−ガラクトース、
Ｄ−フラクトースを用いた場合、並びに対照として無添
加の場合及びＤ−ソルビトールまたはＤ−マンニトール
を用いた場合についても同様に残存率を求めた。Also, D-galactose instead of D-mannose,
Residual rates were similarly determined when D-fructose was used, and when no control was added and when D-sorbitol or D-mannitol was used as a control.
この結果を第３表に示す。 Table 3 shows the results.
実施例４ 硫酸ポリミキシンＢ（8600U/mg）6.977gに酒石酸1.2g
を加え、注射用蒸留水に溶解して全量を1200mlに調整し
た。この液を無菌ろ過し、35ml容量のバイアル瓶に10ml
ずつ充填、密封し、40℃、RH75％の恒温恒湿器に保存
し、１ヵ月後及び２ヵ月後の硫酸ポリミキシンＢの力価
を測定し、初期力価に対する残存率を求めた。 Example 4 Tartaric acid 1.2 g to 6.977 g of polymyxin sulfate B (8600 U / mg)
And dissolved in distilled water for injection to adjust the total volume to 1200 ml. This solution is aseptically filtered, and 10 ml is placed in a 35 ml vial.
The mixture was sealed and stored in a thermo-hygrostat at 40 ° C. and 75% RH. The titer of polymyxin B sulfate after one month and two months was measured, and the residual ratio to the initial titer was determined.
また、酒石酸の代わりにフマル酸、乳酸、DL−リンゴ
酸またはクエン酸を用いた場合、及び対照として無添加
の場合についても同様に残存率を求めた。In addition, the residual rate was similarly obtained when fumaric acid, lactic acid, DL-malic acid or citric acid was used instead of tartaric acid, and when no control was added as a control.
この結果を第４表に示す。 Table 4 shows the results.
実施例５ 硫酸ポリミキシンＢ（8600U/mg）6.977gにポリビニル
ピロリドンＫ−90 12.0gを加え、注射用蒸留水に溶解し
て全量を1200mlに調整した。この液を無菌ろ過し、35ml
容量のバイアル瓶に10mlずつ充填、密封し、40℃、RH75
％の恒温恒湿器に保存し、１ヵ月後及び２ヵ月後の硫酸
ポリミキシンＢの力価を測定し、初期力価に対する残存
率を求めた。 Example 5 12.0 g of polyvinylpyrrolidone K-90 was added to 6.977 g of polymyxin B sulfate (8600 U / mg) and dissolved in distilled water for injection to adjust the total volume to 1200 ml. This liquid is aseptically filtered and 35 ml
Fill vials with a capacity of 10 ml each, seal, 40 ° C, RH75
%, And after one month and two months, the titer of polymyxin sulfate B was measured, and the residual ratio to the initial titer was determined.
また、ポリビニルピロリドンＫ−90の代わりにメチル
セルロース（SM−15）、ヒドロキシプロピルセルロース
（HPC−Ｌ）、ヒドロキシプロピルメチルセルロース（T
C−５）、プルラン、アラビアゴム、ゼラチン、ポリビ
ニルアルコール（ポーバル205）、ポリエチレングリコ
ール（6000）またはポリオキシエチレン硬化ヒマシ油
（HCO−60）を用いた場合、及び対照として無添加の場
合についても同様に残存率を求めた。Also, instead of polyvinylpyrrolidone K-90, methylcellulose (SM-15), hydroxypropylcellulose (HPC-L), hydroxypropylmethylcellulose (T
C-5), when using pullulan, gum arabic, gelatin, polyvinyl alcohol (Poval 205), polyethylene glycol (6000) or polyoxyethylene hydrogenated castor oil (HCO-60), and also without control as a control Similarly, the residual ratio was determined.
この結果を第５表に示す。 Table 5 shows the results.
実施例６ 硫酸ポリミキシンＢ（8600U/mg）6.977gにＬ−グルタ
ミン酸4.8gを加え、生理食塩水に溶解して全量を1200ml
に調整した。この液を無菌ろ過し、35ml容量のバイアル
瓶に10mlずつ充填、密封し、40℃、RH75％の恒温恒湿器
に保存し、１ヵ月後及び２ヵ月後の硫酸ポリミキシンＢ
の力価を測定し、初期力価に対する残存率を求めた。 Example 6 To 6.977 g of polymyxin B sulfate (8600 U / mg), 4.8 g of L-glutamic acid was added and dissolved in physiological saline to make a total volume of 1200 ml.
Was adjusted. This solution was aseptically filtered, filled into vials of 35 ml capacity in 10 ml portions, sealed and stored in a thermo-hygrostat at 40 ° C. and 75% RH. After one and two months, polymyxin B sulfate
Was measured, and the residual ratio to the initial titer was determined.
また、Ｌ−グルタミン酸の代わりにＬ−アスパラギン
酸を用いた場合、並びに対照として無添加の場合及びＬ
−グルタミン酸ナトリウムまたはグリシンを用いた場合
についても同様に残存率を求めた。In addition, when L-aspartic acid was used instead of L-glutamic acid, and when no additive was used as a control,
-In the case where sodium glutamate or glycine was used, the residual ratio was similarly determined.
この結果を第６表に示す。 The results are shown in Table 6.
実施例７ 硫酸コリスチン（19700U/mg）609mgにＬ−アスパラギ
ン酸2.4gを加え、注射用蒸留水に溶解して全量を1200ml
に調整した。この液を無菌ろ過し、35ml容量のバイアル
瓶に10mlずつ充填、密封し、40℃、RH75％の恒温恒湿器
に保存し、１ヵ月後及び２ヵ月後の硫酸コリスチンの力
価を測定し、初期力価に対する残存率を求めた。 Example 7 2.4 g of L-aspartic acid was added to 609 mg of colistin sulfate (19700 U / mg) and dissolved in distilled water for injection to make a total volume of 1200 ml.
Was adjusted. This solution was aseptically filtered, filled into vials having a capacity of 35 ml in 10 ml portions, sealed, and stored in a thermo-hygrostat at 40 ° C. and 75% RH. After 1 month and 2 months, the titer of colistin sulfate was measured. And the residual ratio with respect to the initial titer.
また、Ｌ−アスパラギン酸の代わりにＬ−グルタミン
酸を用いた場合、並びに対照として無添加の場合及びＬ
−グルタミン酸ナトリウムまたはグリシンを用いた場合
についても同様に残存率を求めた。In addition, when L-glutamic acid was used instead of L-aspartic acid, and when no additive was added as a control,
-In the case where sodium glutamate or glycine was used, the residual ratio was similarly determined.
この結果を第７表に示す。 The results are shown in Table 7.
実施例８ コリスチンメタンスルホン酸ナトリウム（12500U/m
g）24.0gにＤ−マンノース6.0gを加え、注射用蒸留水に
溶解して全量を1200mlに調整した。この液を無菌ろ過
し、35ml容量のバイアル瓶に10mlずつ充填、密封し、40
℃、RH75％の恒温恒湿器に保存し、１ヵ月後及び２ヵ月
後のコリスチンメタンスルホン酸ナトリウムの力価を測
定し、初期力価に対する残存率を求めた。 Example 8 colistin sodium methanesulfonate (12500 U / m
g) 6.0 g of D-mannose was added to 24.0 g and dissolved in distilled water for injection to adjust the total amount to 1200 ml. This solution was aseptically filtered, filled into 35 ml vials in 10 ml portions, sealed, and
It was stored in a thermo-hygrostat at 75 ° C. and 75% RH, and the titer of colistin sodium methanesulfonate after one month and two months was measured, and the residual ratio to the initial titer was determined.
また、Ｄ−マンノースの代わりにＬ−グルタミン酸、
酒石酸またはポリビニルピロリドン（Ｋ−90）を用いた
場合、並びに対照として無添加の場合及びＬ−グルタミ
ン酸ナトリウムまたはＤ−マンニトールを用いた場合に
ついても同様に残存率を求めた。Also, L-glutamic acid instead of D-mannose,
Residual rates were similarly determined when tartaric acid or polyvinylpyrrolidone (K-90) was used, and when no control was added and when sodium L-glutamate or D-mannitol was used as a control.
この結果を第８表に示す。 The results are shown in Table 8.
実施例９ 硫酸ポリミキシンＢ（8600U/mg）6.977gにＬ−トレオ
ニン0.6g及びメチルセルロース（SM−15）1.2gを加え、
注射用蒸留水に溶解して全量を1200mlに調整した。この
液を無菌ろ過し、35ml容量のバイアル瓶に10mlずつ充
填、密封し、40℃、RH75％の恒温恒湿器に保存し、１ヵ
月後及び２ヵ月後の硫酸ポリミキシンＢの力価を測定
し、初期力価に対する残存率を求めた。 Example 9 To 6.977 g of polymyxin B sulfate (8600 U / mg), 0.6 g of L-threonine and 1.2 g of methylcellulose (SM-15) were added.
The total amount was adjusted to 1200 ml by dissolving in distilled water for injection. This solution was aseptically filtered, filled into vials of 35 ml capacity in 10 ml portions, sealed, and stored in a thermo-hygrostat at 40 ° C. and 75% RH, and the titer of polymyxin B sulfate after 1 month and 2 months was measured. Then, the residual ratio with respect to the initial titer was determined.
この結果を第９表に示す。 Table 9 shows the results.
［発明の効果］ 本発明のポリミキシン系抗生物質水性溶液は極めて安
定であり、溶液注射剤として有用である。 [Effect of the Invention] The aqueous solution of a polymyxin antibiotic of the present invention is extremely stable and useful as a solution injection.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｋ 47/32 Ａ６１Ｋ 47/32 Ｊ (58)調査した分野(Int.Cl.6，ＤＢ名) ＣＡ（ＳＴＮ)────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. 6 identification code FI A61K 47/32 A61K 47/32 J (58) Investigated field (Int.Cl. 6 , DB name) CA (STN)
Claims (1)
する水性溶液に、水酸基を有するアミノ酸、酸性アミノ
酸、還元性六炭糖類（但し、ブドウ糖を除く）、脂肪族
又は芳香族炭化水素にカルボキシル基のみが置換したも
の、脂肪族炭化水素にカルボキシル基と水酸基のみが置
換したもの、及び水溶性高分子（但し、シクロデキスト
リンを除く）からなる群より選ばれる１種または２種以
上を配合したことを特徴とするポリミキシン系抗生物質
の安定な医薬用水性溶液剤。1. An aqueous solution containing a water-soluble salt of a polymyxin antibiotic, wherein an amino acid having a hydroxyl group, an acidic amino acid, a reducing hexose (excluding glucose), an aliphatic or aromatic hydrocarbon, One or two or more selected from the group consisting of those substituted with only a group, those substituted with only a carboxyl group and a hydroxyl group on an aliphatic hydrocarbon, and water-soluble polymers (excluding cyclodextrin) were blended. A stable pharmaceutical aqueous solution of a polymyxin antibiotic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1181168A JP2844351B2 (en) | 1989-07-13 | 1989-07-13 | Aqueous solution of stable polymyxin antibiotics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1181168A JP2844351B2 (en) | 1989-07-13 | 1989-07-13 | Aqueous solution of stable polymyxin antibiotics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0344333A JPH0344333A (en) | 1991-02-26 |
| JP2844351B2 true JP2844351B2 (en) | 1999-01-06 |
Family
ID=16096076
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1181168A Expired - Lifetime JP2844351B2 (en) | 1989-07-13 | 1989-07-13 | Aqueous solution of stable polymyxin antibiotics |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2844351B2 (en) |
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|---|---|---|---|---|
| CA2107581A1 (en) * | 1992-02-07 | 1993-08-08 | Kiyoshi Sugiyama | Side-effect alleviant |
| TW518219B (en) * | 1996-04-26 | 2003-01-21 | Chugai Pharmaceutical Co Ltd | Erythropoietin solution preparation |
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|---|---|---|---|---|
| EP2564833A1 (en) | 2008-07-28 | 2013-03-06 | Takeda Pharmaceutical Company Limited | Photostabilized pharmaceutical composition |
| US11155532B2 (en) | 2014-02-13 | 2021-10-26 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
| US11247992B2 (en) | 2014-02-13 | 2022-02-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
| US10968221B2 (en) | 2014-07-10 | 2021-04-06 | Incyte Corporation | Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors |
| US10800779B2 (en) | 2015-04-03 | 2020-10-13 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
| US11401272B2 (en) | 2015-04-03 | 2022-08-02 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
| US10723700B2 (en) | 2015-08-12 | 2020-07-28 | Incyte Corporation | Salts of an LSD1 inhibitor |
| US11498900B2 (en) | 2015-08-12 | 2022-11-15 | Incyte Corporation | Salts of an LSD1 inhibitor |
| CN109142760A (en) * | 2018-07-04 | 2019-01-04 | 中国农业大学 | A kind of kit quick and precisely detecting colistin in feed |
| CN109142760B (en) * | 2018-07-04 | 2021-02-02 | 中国农业大学 | Kit for rapidly and accurately detecting colistin in feed |
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| US11512064B2 (en) | 2018-08-31 | 2022-11-29 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0344333A (en) | 1991-02-26 |
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