JP2761005B2 - Injectable composition containing cephalosporin - Google Patents
Injectable composition containing cephalosporinInfo
- Publication number
- JP2761005B2 JP2761005B2 JP63278104A JP27810488A JP2761005B2 JP 2761005 B2 JP2761005 B2 JP 2761005B2 JP 63278104 A JP63278104 A JP 63278104A JP 27810488 A JP27810488 A JP 27810488A JP 2761005 B2 JP2761005 B2 JP 2761005B2
- Authority
- JP
- Japan
- Prior art keywords
- cephalosporin
- weight
- sodium
- hydrochloride
- present
- 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 - Fee Related
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〕 本発明はセファロスポリン含有注射用組成物に関する
もので、医薬の分野において有効に利用されるものであ
る。The present invention relates to a cephalosporin-containing composition for injection, which is effectively used in the field of medicine.
式（Ｉ） によって示されるセファロスポリン、即ち、７β−〔２
−（５−アミノ−1,2,4−チアジアゾール−３−イル）
−（Ｚ）−２−フルオロメトキシイミノアセトアミド〕
−３−〔（Ｅ）−３−（カルバモイルメチルエチルメチ
ルアンモニオ）−１−プロペン−１−イル〕−３−セフ
ェム−４−カルボキシレート及びその非毒性塩（以下本
発明に係るセファロスポリンと呼ぶ）は、グラム陽性菌
からグラム陰性菌、嫌気性菌まで広い抗菌スペクトルを
有し、特に、耐性ブドウ球菌、緑濃菌に対して強い抗菌
力を示す有用性の高い第４世代セフェム系抗生剤で、注
射剤としての使用が期待される（特願昭62−278326号
（特開平１−156984号公報））。Formula (I) Cephalosporin, ie, 7β- [2
-(5-amino-1,2,4-thiadiazol-3-yl)
-(Z) -2-fluoromethoxyiminoacetamide]
-3-[(E) -3- (carbamoylmethylethylmethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate and its non-toxic salts (hereinafter referred to as cephalosporins according to the present invention) Has a broad antibacterial spectrum from gram-positive bacteria to gram-negative bacteria and anaerobic bacteria, and is a highly useful fourth-generation cephem strain that exhibits strong antibacterial activity against resistant staphylococci and green bacilli. Antibiotics are expected to be used as injections (Japanese Patent Application No. 62-278326 (JP-A-1-156984)).
しかし、本物質は化学的に不安定であり、水溶液中に
おいてはもちろん、乾燥粉末状態においても力価減退が
観察される。例えば、用時溶解型凍結乾燥注射剤の製造
時、特に冷却過程で溶解性の低下に基づく凝集、不均一
化が生じ用時溶解性が悪化するためセファロスポリン注
射剤として医療における実用化にあたって問題である。However, this substance is chemically unstable, and a decrease in titer is observed not only in an aqueous solution but also in a dry powder state. For example, at the time of manufacturing a freeze-dried injection preparation for use at the time of use, especially in the cooling process, agglomeration due to a decrease in solubility, non-uniformity occurs, and the solubility at the time of use deteriorates, so practical use in medicine as a cephalosporin injection It is a problem.
従って、本発明の目的は医療において使用できるべ
く、安定性、溶解性の高いセファロスポリン含有注射用
組成物を提供することにある。Accordingly, an object of the present invention is to provide a cephalosporin-containing injectable composition having high stability and solubility, which can be used in medicine.
本発明者らは、本発明に係るセファロスポリンを用時
溶解粉末注射剤とした場合において、その安定性、溶解
性を高める注射用組成物として検討した。その結果、ア
ルギニン、リジン、ヒスチジン、オルニチン、チトルリ
ン、又はそれらの塩酸塩、ヒドロキシプロリン、塩化ナ
トリウム、塩化カリウム、尿素、ニコチン酸アミド、安
息香酸ナトリウム、サリチル酸ナトリウム、タウリンの
中から選ばれる添加剤を単独又は組み合わせて配合する
ことによって上記問題点が著しく改善されることを見出
し本発明を完成するに到った。The present inventors have studied the use of the cephalosporin according to the present invention as an injectable composition for enhancing stability and solubility when used as an injectable powder injection. As a result, arginine, lysine, histidine, ornithine, titrulline, or a hydrochloride thereof, hydroxyproline, sodium chloride, potassium chloride, urea, nicotinamide, sodium benzoate, sodium salicylate, an additive selected from taurine. It has been found that the above problems can be remarkably improved by combining them alone or in combination, and the present invention has been completed.
即ち、本発明は、前記式（Ｉ）でしめされるセファロ
スポリン又はその非毒性塩に、アルギニン、リジン、ヒ
スチジン、オルニチン、チトルリン、又はそれらの塩酸
塩、ヒドロキシプロリン、塩化ナトリウム、塩化カリウ
ム、尿素、ニコチン酸アミド、安息香酸ナトリウム、サ
リチル酸ナトリウム、タウリンの中から選ばれる添加剤
を単独又は組み合わせて配合してなることを特徴とする
セファロスポリン含有注射用組成物に係わるものであ
る。That is, the present invention relates to cephalosporin represented by the formula (I) or a non-toxic salt thereof, which comprises arginine, lysine, histidine, ornithine, titrulline, or a hydrochloride thereof, hydroxyproline, sodium chloride, potassium chloride, The present invention relates to a cephalosporin-containing injectable composition comprising an additive selected from urea, nicotinamide, sodium benzoate, sodium salicylate, and taurine alone or in combination.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明の組成物中の上記添加物の好ましい配合量は、
上記添加物は単独配合する場合、本発明に係るセファロ
スポリン１重量部に対して0.2重量部以上が好ましい。
また上記添加物を組み合わせて配合する場合、アルギニ
ン、リジン、ヒスチジン、オルニチン、チトルリン、又
はそれらの塩酸塩、ヒドロキシプロリンから選ばれる添
加物と、塩化ナトリウム、塩化カリウムの中から選ばれ
る添加物とを組み合わせて配合することが好ましく、こ
れらの配合量は本発明に係るセファロスポリン１重量部
に対し合計で0.2重量部以上が好ましい。Preferred amounts of the additives in the composition of the present invention,
When the above additives are used alone, the amount is preferably 0.2 parts by weight or more based on 1 part by weight of the cephalosporin according to the present invention.
When the above additives are combined and added, arginine, lysine, histidine, ornithine, titrulline, or a hydrochloride thereof, an additive selected from hydroxyproline, and an additive selected from sodium chloride and potassium chloride. It is preferable to combine them in combination, and the amount of these is preferably 0.2 parts by weight or more with respect to 1 part by weight of the cephalosporin according to the present invention.
本発明の組成物の配合方法は、本発明に係るセファロ
スポリンと共に、上記必須成分の他に、医薬製剤の注射
剤構造において通常使用される補助成分、例えば、増量
剤、緩衝化剤、等張化剤等を随意配合すればよい。The compounding method of the composition of the present invention may be, together with the cephalosporin according to the present invention, in addition to the above essential components, auxiliary components usually used in the injection structure of a pharmaceutical preparation, such as a bulking agent and a buffering agent. A toning agent or the like may be optionally added.
本発明の注射用組成物は主として、凍結乾燥粉末とし
て与えられる。例えば、本発明に係るセファロスポリン
とアルギニン又はその塩酸塩を注射用蒸留水に溶解し、
クエン酸緩衝剤又は酸、アルカリで至適pHに調整したの
ち、無菌濾過し、一定量をバイアル又はアンプルに分注
し、凍結乾燥し、密栓又は密封する。また、無菌濾過
後、凍結乾燥して粉末とし、一定量をバイアル又はアン
プルに粉末充填してもよい。The injectable composition of the present invention is mainly provided as a lyophilized powder. For example, dissolving the cephalosporin and arginine or its hydrochloride according to the present invention in distilled water for injection,
After adjusting the pH to the optimum with a citrate buffer or an acid or an alkali, the solution is aseptically filtered, a predetermined amount is dispensed into vials or ampoules, freeze-dried, and sealed or sealed. Alternatively, after aseptic filtration, the powder may be freeze-dried to a powder, and a certain amount may be filled into a vial or ampoule.
以下に記載する実施例によって本発明を具体的に説明
するが、本発明はこれらの実施例に限定されるものでは
ない。The present invention will be described specifically with reference to examples described below, but the present invention is not limited to these examples.
実施例１ 本発明に係るセファロスポリン10g及び尿素2gに予め
用意したpH5の60mMクエン酸ナトリウム40mlを加えて溶
解し、更にpH5に微調整したのち、全量を50mlとした。
この液を無菌濾過したあと、10mlのバイアルに5ml分注
し、凍結乾燥し、密栓した。Example 1 To 10 g of cephalosporin and 2 g of urea according to the present invention, 40 ml of 60 mM sodium citrate of pH 5 prepared in advance was added and dissolved, and after finely adjusting to pH 5, the total amount was adjusted to 50 ml.
After aseptic filtration of this solution, 5 ml was dispensed into a 10 ml vial, lyophilized, and sealed.
実施例２ 本発明に係るセファロスポリン10g、Ｌ−アルギニン
塩酸塩1.5g及び塩化ナトリウム0.5gに予め用意したpH5
の60mMクエン酸ナトリウム40mlを加えて、溶解し、更に
pH5に微調整したのち、全量50mlとした。この液を無菌
濾過したのち、10mlのバイアルに5ml分注し、凍結乾燥
し、密栓した。Example 2 10 g of cephalosporin according to the present invention, 1.5 g of L-arginine hydrochloride and 0.5 g of sodium chloride prepared in advance at pH 5
Add 40 ml of 60 mM sodium citrate and dissolve
After fine adjustment to pH 5, the total volume was adjusted to 50 ml. After aseptic filtration of this solution, 5 ml was dispensed into a 10 ml vial, lyophilized, and sealed.
本発明に係るセファロスポリンを用時溶解粉末注射剤
とした場合における安定性及び用時溶解性を高める効果
を次の実験例を示す。The following experimental examples show the effect of increasing the stability and the solubility at the time of use when the cephalosporin according to the present invention is used as a powdery injection at the time of use.
実験例１ 本発明に係るセファロスポリンを試験管に、それぞれ
200mg（１重量部）ずつとり、これにＬ−アルギニン塩
酸塩、Ｌ−リジン塩酸塩、Ｌ−ヒスチジン塩酸塩、Ｌ−
チトルリン、ヒドロキシプロリン、塩化ナトリウム、塩
化カリウム、尿素、ニコチン酸アミド、安息香酸ナトリ
ウム、サリチル酸ナトリウム、タウリン、Ｌ−オルニチ
ン塩酸塩をそれぞれ40mg（0.2重量部）、100mg（0.5重
量部）、200mg（１重量部）を加え、pH4の60mMクエン酸
緩衝液1.6mlを加えて溶解し、pH4に微調整した後、全量
を2mlとした。Experimental Example 1 The cephalosporins according to the present invention were placed in test tubes, respectively.
Take 200 mg (1 part by weight) each, and add L-arginine hydrochloride, L-lysine hydrochloride, L-histidine hydrochloride, L-
Titraline, hydroxyproline, sodium chloride, potassium chloride, urea, nicotinamide, sodium benzoate, sodium salicylate, taurine, L-ornithine hydrochloride are 40 mg (0.2 parts by weight), 100 mg (0.5 parts by weight), 200 mg (1 part), respectively. Parts by weight), and 1.6 ml of a 60 mM citrate buffer at pH 4 was added to dissolve the mixture. The mixture was finely adjusted to pH 4 and the total amount was adjusted to 2 ml.
次に、メンブランフィルターで濾過し、2mlのバイア
ルに0.5mlずつ分注し、凍結乾燥し、密栓して検体試料
とした。Next, the solution was filtered through a membrane filter, dispensed in 0.5 ml portions into 2 ml vials, freeze-dried, sealed and used as a specimen sample.
別に、セファロスポリン200mgをとり、60mMクエン酸
ナトリウムで溶解し2mlとし、同様に0.5mlずつ分注し、
凍結乾燥し、密栓して対照試料とした。Separately, take 200 mg of cephalosporin, dissolve in 60 mM sodium citrate to 2 ml, and similarly dispense 0.5 ml each,
Lyophilized, sealed and used as a control sample.
検体試料及び対照試料を50℃で７日間保存し、溶解性
の確認と安定性を測定した。The test sample and the control sample were stored at 50 ° C. for 7 days, and the solubility was confirmed and the stability was measured.
即ち、溶解性については、各試料毎に0.5mlの注射用
蒸留水を加え、凍結乾燥粉末が溶解するか否かを確認し
た。That is, regarding solubility, 0.5 ml of distilled water for injection was added to each sample, and it was confirmed whether or not the lyophilized powder was dissolved.
また、安定性については、各試料の残存率を下記の高
速液体クロマトグラフィーの条件により測定した。な
お、測定は、冷凍保存（−30℃）した試料のピーク高さ
を、内部標準物質との比により求めた。As for the stability, the residual ratio of each sample was measured under the following high-performance liquid chromatography conditions. In addition, the measurement measured the peak height of the sample preserve | saved frozen (-30 degreeC) by the ratio with an internal standard substance.
高速液体クロマトグラフィー条件 固定相:YMC−A302 ODS 移動相：メタノール：水：酢酸アンモニウム＝100:900:
1 結果を表１に示す。High-performance liquid chromatography conditions Stationary phase: YMC-A302 ODS Mobile phase: methanol: water: ammonium acetate = 100: 900:
1 The results are shown in Table 1.
表１より上記添加剤を加えることにより本発明に係る
セファロスポリンの溶解性、安定性が改善されることが
明らかである。 From Table 1, it is clear that the addition of the above additives improves the solubility and stability of the cephalosporin according to the present invention.
実験例２ 本発明に係るセファロスポリン200mg（１重量部）に
対して、Ｌ−アルギニン塩酸塩及び塩化ナトリウムを表
２に示す重量比で添加し、実験例１と同様にpH4の60mM
クエン酸緩衝液1.6mlを加えて溶解し2mlとした。Experimental Example 2 To 200 mg (1 part by weight) of the cephalosporin according to the present invention, L-arginine hydrochloride and sodium chloride were added at the weight ratio shown in Table 2, and 60 mM of pH 4 was obtained in the same manner as in Experimental Example 1.
1.6 ml of citrate buffer was added and dissolved to make 2 ml.
メンブランフィルターで濾過し、2mlのバイアルに0.5
ml分注し、凍結乾燥し、密栓し、検体試料とした。Filter through a membrane filter and add 0.5 to 2 ml vial.
ml was dispensed, lyophilized, sealed and used as a sample.
各試料を55℃で７日間保存し、以下実験例１と同様に
溶解性と安定性の確認を行った。Each sample was stored at 55 ° C. for 7 days, and the solubility and stability were confirmed in the same manner as in Experimental Example 1.
表２に結果を示す。 Table 2 shows the results.
表２より、Ｌ−アルギニン塩酸塩及び塩化ナトリウム
を組み合わせた添加物を加えることにより、安定性及び
溶解性が向上したことがわかる。 Table 2 shows that the stability and solubility were improved by adding an additive combining L-arginine hydrochloride and sodium chloride.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) A61K 31/545 A61K 9/08 ＣＡ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. 6 , DB name) A61K 31/545 A61K 9/08 CA (STN)
Claims (3)
−（５−アミノ−1,2,4−チアジアゾール−３−イル）
−（Ｚ）−２−フルオロメトキシイミノアセトアミド〕
−３−〔（Ｅ）−３−（カルバモイルメチルエチルメチ
ルアンモニオ）−１−プロペン−１−イル〕−３−セフ
ェム−４−カルボキシレート、又はその非毒性塩に、ア
ルギニン、リジン、ヒスチジン、オルニチン、チトルリ
ン、又はそれらの塩酸塩、ヒドロキシプロリン、塩化ナ
トリウム、塩化カリウム、尿素、ニコチン酸アミド、安
息香酸ナトリウム、サリチル酸ナトリウム、タウリンの
中から選ばれる添加剤を単独又は組み合わせて配合して
なることを特徴とするセファロスポリン含有注射用組成
物。(1) Expression Cephalosporin, ie, 7β- [2
-(5-amino-1,2,4-thiadiazol-3-yl)
-(Z) -2-fluoromethoxyiminoacetamide]
-3-[(E) -3- (carbamoylmethylethylmethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate or a non-toxic salt thereof includes arginine, lysine, histidine, Ornithine, titrulline, or their hydrochloride, hydroxyproline, sodium chloride, potassium chloride, urea, nicotinamide, sodium benzoate, sodium salicylate, or a mixture of additives alone or in combination with taurine A cephalosporin-containing injectable composition comprising:
チン、チトルリン、又はそれらの塩酸塩、ヒドロキシプ
ロリン、塩化ナトリウム、塩化カリウム、尿素、ニコチ
ン酸アミド、安息香酸ナトリウム、サリチル酸ナトリウ
ム、タウリンの中から選ばれる添加剤を単独配合する場
合、その配合量がセファロスポリン又はその非毒性塩１
重量部に対し0.2重量部以上である請求項１記載のセフ
ァロスポリン含有注射用組成物。2. An addition selected from arginine, lysine, histidine, ornithine, titrulline, or a hydrochloride thereof, hydroxyproline, sodium chloride, potassium chloride, urea, nicotinamide, sodium benzoate, sodium salicylate, and taurine. When the agent is used alone, the amount of cephalosporin or its non-toxic salt 1
The cephalosporin-containing injectable composition according to claim 1, wherein the amount is 0.2 parts by weight or more based on parts by weight.
チン、チトルリン、又はそれらの塩酸塩、ヒドロキシプ
ロリンから選ばれる添加剤と、塩化ナトリウム、塩化カ
リウムの中から選ばれる添加剤とを組み合わせて配合
し、これらの配合量がセファロスポリン又はその非毒性
塩１重量部に対し合計で0.2重量部以上である請求項１
記載のセファロスポリン含有注射用組成物。3. An additive selected from arginine, lysine, histidine, ornithine, titrulline, or a hydrochloride thereof or hydroxyproline, and an additive selected from sodium chloride and potassium chloride. The total amount of the compound is 0.2 parts by weight or more based on 1 part by weight of cephalosporin or a nontoxic salt thereof.
A cephalosporin-containing injectable composition as described in the above.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63278104A JP2761005B2 (en) | 1988-11-02 | 1988-11-02 | Injectable composition containing cephalosporin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63278104A JP2761005B2 (en) | 1988-11-02 | 1988-11-02 | Injectable composition containing cephalosporin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02124823A JPH02124823A (en) | 1990-05-14 |
| JP2761005B2 true JP2761005B2 (en) | 1998-06-04 |
Family
ID=17592685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63278104A Expired - Fee Related JP2761005B2 (en) | 1988-11-02 | 1988-11-02 | Injectable composition containing cephalosporin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2761005B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100188318B1 (en) * | 1993-04-28 | 1999-06-01 | 고오야 마사시 | Stabilized injection and method of stabilizing injection |
| JPH0840907A (en) * | 1994-08-03 | 1996-02-13 | Meiji Seika Kaisha Ltd | Cephalosporin injection |
| DE102007002924A1 (en) | 2007-01-19 | 2008-07-24 | Bayer Healthcare Ag | ß-lactam-containing formulations with increased stability in aqueous solution |
| BRPI0816412A2 (en) * | 2007-09-21 | 2017-05-16 | Forest Laboratories Holdings Ltd | dosage form and method for treating a bacterial infection |
-
1988
- 1988-11-02 JP JP63278104A patent/JP2761005B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02124823A (en) | 1990-05-14 |
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