JPH04338332A - Cephalosporin injection and its preparation - Google Patents
Cephalosporin injection and its preparationInfo
- Publication number
- JPH04338332A JPH04338332A JP3107386A JP10738691A JPH04338332A JP H04338332 A JPH04338332 A JP H04338332A JP 3107386 A JP3107386 A JP 3107386A JP 10738691 A JP10738691 A JP 10738691A JP H04338332 A JPH04338332 A JP H04338332A
- Authority
- JP
- Japan
- Prior art keywords
- dissolved
- injection
- solution
- hydrochloride
- ethyl alcohol
- 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.)
- Granted
Links
- 238000002347 injection Methods 0.000 title claims abstract description 27
- 239000007924 injection Substances 0.000 title claims abstract description 27
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 6
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 6
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000000243 solution Substances 0.000 claims abstract description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 18
- 235000019441 ethanol Nutrition 0.000 claims abstract description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 14
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 9
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- 238000004108 freeze drying Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000011780 sodium chloride Substances 0.000 claims abstract description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 6
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical compound N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- XIIRUKYIKAFBEZ-XNWCZRBMSA-N (2z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide Chemical compound CO\N=C(/C(N)=O)C1=NSC(N)=N1 XIIRUKYIKAFBEZ-XNWCZRBMSA-N 0.000 claims description 2
- -1 carboxylate hydrochloride Chemical class 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 21
- 208000015181 infectious disease Diseases 0.000 abstract description 6
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 239000012528 membrane Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 241000192125 Firmicutes Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- JEZLXOPWYADHOP-SSDOTTSWSA-N (6r)-4-methylidene-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound C1=CC(=C)S[C@@H]2CC(=O)N21 JEZLXOPWYADHOP-SSDOTTSWSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960002660 mepivacaine hydrochloride Drugs 0.000 description 2
- RETIMRUQNCDCQB-UHFFFAOYSA-N mepivacaine hydrochloride Chemical compound Cl.CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C RETIMRUQNCDCQB-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010061126 Escherichia infection Diseases 0.000 description 1
- 206010061977 Genital infection female Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010053636 Obstetric infection Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000020612 escherichia coli infection Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は、セファロスポリン注射
剤およびその製造法に関する。従って、本発明は医薬品
の分野において利用される。TECHNICAL FIELD The present invention relates to a cephalosporin injection and a method for producing the same. Therefore, the present invention finds use in the pharmaceutical field.
【０００２】0002
【従来の技術および課題】特開平１−２５０３２２号に
開示される式（Ｉ）：[Prior Art and Problems] Formula (I) disclosed in JP-A-1-250322:
【化１】
によって示されるセファロスポリン、すなわち、７β−
［２−（５−アミノ−１，２，４−チアジアゾール−３
−イル）−２（Ｚ）−メトキシイミノアセタミド］−３
−［（１−イミダゾ［１，２−ｂ］ピリダジニウム）メ
チル］−３−セフエム−４−カルボキシレート・塩酸塩
［以下、単に、塩酸塩（Ｉ）と、また塩酸塩を形成して
いないものをフリー体と略す場合がある］は、グラム陽
性菌のみならず、緑膿菌を含むグラム陰性菌に対しても
強い抗菌力を示す他、メチレン−セフェム耐性ブドウ球
（ＭＲＳＡ）感染症に対しても、比較的強い有効性をし
めすことから、抗菌剤として極めて有用な抗生物質であ
り、該出願においては、炭酸ナトリウムおよび塩化ナト
リウムと共にバイアルに充填し、用時溶解型粉末注射剤
として用いる例が記載されている。A cephalosporin represented by: 7β-
[2-(5-amino-1,2,4-thiadiazole-3
-yl)-2(Z)-methoxyiminoacetamide]-3
-[(1-imidazo[1,2-b]pyridazinium)methyl]-3-cephem-4-carboxylate hydrochloride [hereinafter simply referred to as hydrochloride (I) and those that do not form a hydrochloride ] has strong antibacterial activity against not only Gram-positive bacteria but also Gram-negative bacteria including Pseudomonas aeruginosa, and is effective against methylene-cephem-resistant staphylococcus (MRSA) infections. However, it is an extremely useful antibiotic as an antibacterial agent, as it shows relatively strong efficacy.In this application, it is used as a powder injection that can be dissolved at the time of use by being filled into a vial with sodium carbonate and sodium chloride. is listed.
【０００３】しかしながら、フリー体（両性イオン）よ
り該塩酸塩（Ｉ）を大規模に製造する場合、対応するフ
リー体に極めて難溶性の結晶型のものが生じ、それが極
微量でも混在すると、用時溶解型粉末注射剤の溶解時に
該フリー体の結晶が析出し、注射剤として投与すること
ができなくなることがある。この問題に対し、未だ満足
すべき解決手段が得られていない。However, when the hydrochloride (I) is produced on a large scale from the free form (zwitterion), an extremely poorly soluble crystal form is produced in the corresponding free form, and if even a trace amount of this is present, When a ready-to-use powder injection is dissolved, crystals of the free form may precipitate, making it impossible to administer it as an injection. A satisfactory solution to this problem has not yet been found.
【０００４】0004
【課題を解決するための手段】かかる事情にかんがみ、
本発明者らは塩酸塩（Ｉ）の用時溶解性に優れた粉末注
射剤を得るべく、鋭意検討した。その結果、塩酸塩（Ｉ
）と塩基性炭酸塩とを水またはエチルアルコール水溶液
で溶解し、凍結乾燥することにより、塩酸塩（Ｉ）製造
に用いるフリー体の結晶型にかかわりなく、用時溶解性
に優れた注射剤が得られることを知り、本発明を完成す
るに至った。[Means for solving the problem] Considering the circumstances,
The present inventors have made extensive studies to obtain a powder injection of hydrochloride (I) with excellent solubility during use. As a result, hydrochloride (I
) and a basic carbonate in water or an aqueous ethyl alcohol solution and freeze-drying, an injection with excellent solubility at the time of use can be obtained, regardless of the crystal form of the free form used to produce hydrochloride (I). After realizing that the present invention can be obtained, the present invention was completed.
【０００５】すなわち、本発明は、塩酸塩（Ｉ）、すな
わち、７β−［２−（５−アミノ−１，２，４−チアジ
アゾール−３−イル）−２（Ｚ）−メトキシイミノアセ
トアミド］−３−［１−イミダゾ［１，２−ｂ］ピリダ
ジニウム）メチル］−３−セフェム−４−カルボキシレ
ート・塩酸塩と塩基性炭酸塩とを水またはエチルアルコ
ール水溶液に溶解した溶液を凍結乾燥することを特徴と
するセファロスポリン注射剤の製造法および該製造法に
よって得られる注射剤、特に、用時溶解型注射剤を提供
するもので、本発明においては、要すれば、塩酸塩（Ｉ
）と塩基性炭酸塩とを水またはエチルアルコール水溶液
に溶解した溶液に、凍結乾燥前に溶解補助剤をさらに添
加、溶解してもよい。That is, the present invention provides hydrochloride (I), namely, 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamide]- Freeze-drying a solution in which 3-[1-imidazo[1,2-b]pyridazinium)methyl]-3-cephem-4-carboxylate hydrochloride and basic carbonate are dissolved in water or an aqueous ethyl alcohol solution. The present invention provides a method for producing a cephalosporin injection characterized by
) and a basic carbonate dissolved in water or an aqueous ethyl alcohol solution, a solubilizing agent may be further added and dissolved before freeze-drying.
【０００６】用いる塩酸塩（Ｉ）は前記特開平１−２５
０３２２号の方法に記載のとおりの方法で製造できる。
塩基性炭酸塩としては、例えば、炭酸ナトリウム、炭酸
水素ナトリウム等が挙げられ、注射用に適したグレード
のものが使用される。塩基性炭酸塩は単独でも、２種以
上を併用してもよく、通常、該塩酸塩（Ｉ）１当量に対
して０．５〜５当量が用いられる。The hydrochloride (I) used is disclosed in the above-mentioned JP-A-1-25
It can be produced by the method described in No. 0322. Examples of the basic carbonate include sodium carbonate and sodium hydrogen carbonate, and those of a grade suitable for injection are used. The basic carbonate may be used alone or in combination of two or more kinds, and is usually used in an amount of 0.5 to 5 equivalents per equivalent of the hydrochloride (I).
【０００７】塩酸塩（Ｉ）と塩基性炭酸塩の溶解に用い
る水は例えば注射用水でよく、また、エチルアルコール
水溶液としては、通常、４〜５０容量％、好ましくは１
０〜３０容量％程度のエチルアルコール水溶液が用いら
れ、具体的には注射用グレードのエチルアルコールの注
射用水溶液などが用いられる。通常、塩酸塩（Ｉ）１当
量に対して通常、水２０〜３００当量またはエチルアル
コール３〜６当量の割合で用いる。水を用いる場合は、
２０〜６０℃、好ましくは３０〜５０℃で加熱溶解する
か、該温度に加熱した水を用いることが好ましい。本発
明においては、要すれば、溶解補助剤をさらに加えても
よい。かかる溶解補助剤としては、例えば、塩化ナトリ
ウム、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、ポリエチレングリコール、プロピレン
グリコール等、好ましくは、例えば塩化ナトリウムが挙
げられる。これらの溶解補助剤は単独でも、２種以上を
併用してもよく、通常、塩酸塩（Ｉ）１当量に対して０
．１〜５当量用いられる。凍結乾燥は自体公知の方法に
従って行うことができる。The water used for dissolving the hydrochloride (I) and the basic carbonate may be, for example, water for injection, and the ethyl alcohol aqueous solution is usually 4 to 50% by volume, preferably 1% by volume.
An aqueous solution of ethyl alcohol of about 0 to 30% by volume is used, and specifically, an aqueous solution of ethyl alcohol for injection of injection grade is used. Usually, it is used in a ratio of 20 to 300 equivalents of water or 3 to 6 equivalents of ethyl alcohol per 1 equivalent of hydrochloride (I). When using water,
It is preferable to melt by heating at 20 to 60°C, preferably 30 to 50°C, or to use water heated to this temperature. In the present invention, a solubilizing agent may be further added if necessary. Such solubilizing agents include, for example, sodium chloride, nicotinamide, sodium benzoate, sodium salicylate, polyethylene glycol, propylene glycol, and preferably, for example, sodium chloride. These solubilizing agents may be used alone or in combination of two or more, and are usually used in an amount of 0 per equivalent of hydrochloride (I).
．． 1 to 5 equivalents are used. Freeze-drying can be performed according to a method known per se.
【０００８】かくして、本発明の注射剤は、例えば塩酸
塩（Ｉ）と塩基性炭酸塩を粉末状態で混合し、水または
エチルアルコール水溶液に溶解した後、あるいはそれぞ
れを予め水またはエチルアルコール水溶液に溶解し、混
合した後、要すれば、溶解補助剤を添加し、溶解後、無
菌ろ過し、一定量をバイアル（バイアル内真空度は通常
約０〜５００ｍｍＨｇ、好ましくは約０〜１００ｍｍＨ
ｇ）またはアンプル等に分注し、凍結乾燥して製造され
る。また、凍結乾燥後微粉化してバイアルまたはアンン
プル等に粉末充填してもよい。本発明注射剤の製造は、
密封条件下に行うのが好ましい。また、例えば塩酸リド
カイン、塩酸メピバカイン等の局所麻酔剤などの自体公
知の医薬、添加物をさらに必要により本発明の効果を損
なわない範囲で配合して製造することもできる。これを
用時に注射用蒸留水、生理食塩液またはブドウ糖液など
の溶解液を加えて、溶解し、投与する。溶解液の添加量
は、フリー体１ｇに体して通常１〜１００ミリリットル
（１０ｍｇ／ミリリットル〜１ｇ／ミリリットル）であ
る。本発明の注射剤は、グラム陽性菌のみならず、緑膿
菌を含むグラム陰性菌に対しても強い抗菌力をしめす他
、メチレン−セフェム耐性ブドウ球（ＭＲＳＡ）感染症
に対しても非常に有効であり、安全性も高い。なお、本
発明の注射剤には、注用の剤形のものも包含される。従
って、本発明の注射剤は、細菌感染症治療剤として、例
えば人や他の哺乳動物の呼吸感染症、尿路感染症、化膿
性疾患、胆道感染症、腸内感染症、産婦人科感染症、耳
鼻科感染症、外科感染症等の治療および予防に用いるこ
とができる。例えば、人、マウス、ラット、犬などの温
血動物に対してグラム陽性菌やグラム陰性菌に起因する
感染性疾患の治療予防薬として筋肉内注射あるいは静脈
内注射により投与される。具体的には、人あるいはマウ
スのエシリヒア・コリ感染による尿路感染症に対しては
、フリー体に換算して約５〜５０ｍｇ／ｋｇを、好まし
くは１日３〜４回に分けて筋肉内または静脈内注射すれ
ばよい。[0008] Thus, the injection of the present invention can be prepared, for example, by mixing hydrochloride (I) and a basic carbonate in powder form and dissolving the mixture in water or an aqueous ethyl alcohol solution, or by dissolving each in water or an aqueous ethyl alcohol solution in advance. After dissolving and mixing, if necessary, a solubilizing agent is added, and after dissolution, sterile filtration is performed, and a certain amount is poured into a vial (the degree of vacuum in the vial is usually about 0 to 500 mmHg, preferably about 0 to 100 mmH).
g) or by dispensing into ampoules and freeze-drying. Alternatively, the powder may be pulverized after freeze-drying and filled into vials, ampoules, or the like. The production of the injection of the present invention is as follows:
Preferably, it is carried out under sealed conditions. In addition, if necessary, it is possible to further incorporate known medicines and additives, such as local anesthetics such as lidocaine hydrochloride and mepivacaine hydrochloride, to the extent that they do not impair the effects of the present invention. At the time of use, this is dissolved and administered by adding a dissolving solution such as distilled water for injection, physiological saline, or glucose solution. The amount of the solution added is usually 1 to 100 ml (10 mg/ml to 1 g/ml) per 1 g of free body. The injectable preparation of the present invention exhibits strong antibacterial activity against not only Gram-positive bacteria but also Gram-negative bacteria including Pseudomonas aeruginosa, and is also highly effective against methylene-cephem-resistant staphylococcal (MRSA) infections. It is effective and highly safe. Incidentally, the injection of the present invention also includes a dosage form for injection. Therefore, the injection of the present invention can be used as a therapeutic agent for bacterial infections, such as respiratory infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, and obstetric and gynecological infections in humans and other mammals. It can be used for the treatment and prevention of otolaryngological infections, otorhinolaryngological infections, surgical infections, etc. For example, it is administered to warm-blooded animals such as humans, mice, rats, and dogs by intramuscular or intravenous injection as a preventive agent for infectious diseases caused by Gram-positive bacteria or Gram-negative bacteria. Specifically, for urinary tract infections caused by Escherichia coli infection in humans or mice, approximately 5 to 50 mg/kg of free body should be administered intramuscularly, preferably in 3 to 4 divided doses per day. Or it can be injected intravenously.
【０００９】[0009]
【実施例】以下に、参考例および実施例を挙げて、本発
明をさらに詳しく説明する。例中の％は容量％を示す。
参考例
塩酸塩（Ｉ）１．１ｇに炭酸ナトリウム２０６ｍｇを配
合し、注射用蒸留水５ｍｌ加えて溶解するとフリー体が
析出し、澄明な溶液が得られなかった。
実施例１
塩酸塩（Ｉ）１．１ｇと炭酸ナトリウム２０６ｍｇを密
封容器中で混合し、１８％エチルアルコール水溶液３ミ
リリットルを注入し、溶解した後、塩化ナトリウム１２
０ｍｇを添加、溶解し、メンブランフィルターでろ過し
、パイアルに分注し、凍結乾燥した。本凍結乾燥品に注
射用蒸留水５ミリリットル加えて溶解すると、澄明にと
けた。[Examples] The present invention will be explained in more detail below with reference to reference examples and examples. % in the examples indicates volume %. Reference Example When 206 mg of sodium carbonate was blended with 1.1 g of hydrochloride (I) and dissolved by adding 5 ml of distilled water for injection, free bodies were precipitated and a clear solution could not be obtained. Example 1 1.1 g of hydrochloride (I) and 206 mg of sodium carbonate were mixed in a sealed container, 3 ml of 18% ethyl alcohol aqueous solution was poured in, and after dissolving, 12 g of sodium chloride
0 mg was added and dissolved, filtered through a membrane filter, dispensed into vials, and freeze-dried. When 5 ml of distilled water for injection was added to this freeze-dried product and dissolved, it dissolved clearly.
【００１０】実施例２
塩酸塩（Ｉ）１．１ｇと炭酸ナトリウム２０６ｍｇを密
封容器中で混合し、２６％エチルアルコール水溶液２ミ
リリットルを注入し、更に注射用水５ミリリットルを加
え溶解した後、ニコチン酸アミド２００ｍｇを添加、溶
解し、メンブランフィルターでろ過し、トレイに厚さ８
ｍｍ位に分注し、凍結乾燥した。この乾燥物を飾過・粉
砕後、アンプルに充填した。本品に生理食塩液５ｍｌ加
えて溶解すると澄明にとけた。
実施例３
塩酸塩（Ｉ）０．５ｇと炭酸ナトリウム１０３ｍｇを密
封容器中で混合し、４０℃の温水３ミリリットルを注入
し、溶解した後、安息香酸ナトリウム２００ｍｇを添加
溶解し、メンブランフィルターでろ過し、パイアルに分
注し、凍結乾燥した。本凍結乾燥品に塩酸メピバカイン
液３ミリリットル加えて溶解すると澄明にとけた。
実施例４
塩酸塩（Ｉ）１．１ｇに炭酸ナトリウム２０６ｍｇを密
封容器中で混合し、２６．３％エチルアルコール水溶液
２ミリリットルを注入しよく混合した。更に注射用蒸留
水６ミリリットルおよび塩化ナトリウム１２０ｍｇを添
加、溶解し、メンブランフィルターで濾過し、バイアル
に分注し、凍結乾燥した。本凍結乾燥品に注射用蒸留水
５ミリリットルを加えて溶解すると、透明にとけた。Example 2 1.1 g of hydrochloride (I) and 206 mg of sodium carbonate were mixed in a sealed container, 2 ml of a 26% ethyl alcohol aqueous solution was poured into the container, and 5 ml of water for injection was added and dissolved, followed by nicotinic acid. Add 200 mg of amide, dissolve, filter through a membrane filter, and place on a tray with a thickness of 8.
The mixture was dispensed into 3 mm portions and freeze-dried. This dried product was filtered and crushed, and then filled into ampoules. When 5 ml of physiological saline was added to this product and dissolved, it dissolved clearly. Example 3 0.5 g of hydrochloride (I) and 103 mg of sodium carbonate were mixed in a sealed container, and 3 ml of 40°C warm water was poured into the mixture to dissolve it. Then, 200 mg of sodium benzoate was added and dissolved, and filtered with a membrane filter. It was then dispensed into vials and lyophilized. When 3 ml of mepivacaine hydrochloride solution was added to this freeze-dried product and dissolved, it dissolved clearly. Example 4 1.1 g of hydrochloride (I) and 206 mg of sodium carbonate were mixed in a sealed container, and 2 ml of a 26.3% ethyl alcohol aqueous solution was poured into the mixture and mixed well. Furthermore, 6 ml of distilled water for injection and 120 mg of sodium chloride were added and dissolved, filtered through a membrane filter, dispensed into vials, and freeze-dried. When 5 ml of distilled water for injection was added to this freeze-dried product and dissolved, it became transparent.
【００１１】[0011]
【発明の効果】塩酸塩（Ｉ）を用時溶解型注射剤として
使用する場合、特に、フリー体から塩酸塩を大規模に製
造する際のフリー体の結晶型の転移により、用時溶解の
際に難溶性のフリー体の結晶が析出して注射剤として使
用することが不可能になる場合があり、本発明はこの結
晶析出を抑制し、これにより該抗菌剤をフリー体の結晶
型にかかわりなく用時溶解型注射剤として使用すること
が可能となった。Effects of the Invention When hydrochloride (I) is used as a ready-to-dissolve injection, the transformation of the crystal form of the free form during large-scale production of hydrochloride from the free form makes it easier to dissolve at the time of use. In some cases, poorly soluble free crystals may precipitate, making it impossible to use as an injection.The present invention suppresses this crystal precipitation, thereby converting the antibacterial agent into a free crystal form. It is now possible to use the product as an injection that dissolves at the time of use.
Claims (7)
４−チアジアゾール−３−イル）−２（Ｚ）−メトキシ
イミノアセトアミド］−３−［（１−イミダゾ［１，２
−ｂ］ピリダジニウム）メチル］−３−セフェム−４−
カルボキシレート・塩酸塩と塩基性炭酸塩とを水または
エチルアルコール水溶液に溶解した溶液を凍結乾燥する
ことを特徴とするセファロスポリン注射剤の製造法。[Claim 1] 7β-[2-(5-amino-1,2,
4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamide]-3-[(1-imidazo[1,2
-b]pyridazinium)methyl]-3-cephem-4-
A method for producing a cephalosporin injection, which comprises lyophilizing a solution in which a carboxylate hydrochloride and a basic carbonate are dissolved in water or an aqueous ethyl alcohol solution.
炭酸水素ナトリウムである請求項１記載の製造法。2. The method according to claim 1, wherein the basic carbonate is sodium carbonate or sodium bicarbonate.
量％エチルアルコール水溶液である請求項１記載の製造
法。3. The method according to claim 1, wherein the aqueous ethyl alcohol solution is a 4 to 50% by volume ethyl alcohol aqueous solution.
結乾燥させる請求項１記載の製造法。4. The method according to claim 1, wherein a solution dissolved in water at 20 to 60° C. is freeze-dried.
解した溶液に、凍結乾燥前に溶解補助剤を添加、溶解す
る請求項１記載の製造法。5. The production method according to claim 1, wherein a solubilizing agent is added and dissolved in the solution in water or an aqueous ethyl alcohol solution before freeze-drying.
求項５記載の製造法。6. The production method according to claim 5, wherein the solubilizing agent is sodium chloride.
射剤。7. An injection prepared by the method according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3107386A JP2919112B2 (en) | 1991-05-13 | 1991-05-13 | Cephalosporin injection and production method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3107386A JP2919112B2 (en) | 1991-05-13 | 1991-05-13 | Cephalosporin injection and production method thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP00911599A Division JP3737642B2 (en) | 1999-01-18 | 1999-01-18 | Cephalosporin injection and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04338332A true JPH04338332A (en) | 1992-11-25 |
| JP2919112B2 JP2919112B2 (en) | 1999-07-12 |
Family
ID=14457816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3107386A Expired - Fee Related JP2919112B2 (en) | 1991-05-13 | 1991-05-13 | Cephalosporin injection and production method thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2919112B2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6111098A (en) * | 1994-05-02 | 2000-08-29 | Shionogi & Co., Ltd. | Crystal of pyrrolidylthiocarbapenem derivative, lyophilized preparation containing said crystal, and process for producing the same |
| WO2002042266A3 (en) * | 2000-11-22 | 2002-08-15 | Biochemie Gmbh | Process for the production of ceftifur sodium salt |
| WO2004096279A1 (en) * | 2003-04-28 | 2004-11-11 | Takeda Pharmaceutical Company Limited | Composition for injection |
| JP2005239700A (en) * | 2003-04-28 | 2005-09-08 | Takeda Chem Ind Ltd | Composition for injection |
| WO2006007835A3 (en) * | 2004-07-21 | 2006-04-13 | Helmut Kasch | Ammonium salts and ammonium salt/mineral salt clathrate compounds for use as vehicle and effective form for pharmaco-medical applications and for use as phase transfer agents for chemical applications |
| WO2009138847A3 (en) * | 2008-05-14 | 2010-04-22 | Orchid Chemicals And Pharmaceuticals Ltd. | An improved process for the preparation of cefozopran |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4456177B2 (en) | 2007-09-04 | 2010-04-28 | 明治製菓株式会社 | Injection, injection solution and injection kit preparation |
-
1991
- 1991-05-13 JP JP3107386A patent/JP2919112B2/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6111098A (en) * | 1994-05-02 | 2000-08-29 | Shionogi & Co., Ltd. | Crystal of pyrrolidylthiocarbapenem derivative, lyophilized preparation containing said crystal, and process for producing the same |
| WO2002042266A3 (en) * | 2000-11-22 | 2002-08-15 | Biochemie Gmbh | Process for the production of ceftifur sodium salt |
| WO2004096279A1 (en) * | 2003-04-28 | 2004-11-11 | Takeda Pharmaceutical Company Limited | Composition for injection |
| JP2005239700A (en) * | 2003-04-28 | 2005-09-08 | Takeda Chem Ind Ltd | Composition for injection |
| WO2006007835A3 (en) * | 2004-07-21 | 2006-04-13 | Helmut Kasch | Ammonium salts and ammonium salt/mineral salt clathrate compounds for use as vehicle and effective form for pharmaco-medical applications and for use as phase transfer agents for chemical applications |
| JP2008506723A (en) * | 2004-07-21 | 2008-03-06 | カシュ，ヘルムート | Ammonium salts and ammonium salt-mineral salt clathrate compounds as pharmaceutical carriers and agents and chemical phase transfer agents |
| CN1989098B (en) | 2004-07-21 | 2011-12-07 | 赫尔穆特·卡施 | Ammonium salts and ammonium/inorganic salt clathrates as carriers and active forms for pharmaceutical-medical applications and as phase transfer agents for chemical applications |
| WO2009138847A3 (en) * | 2008-05-14 | 2010-04-22 | Orchid Chemicals And Pharmaceuticals Ltd. | An improved process for the preparation of cefozopran |
| JP2011520866A (en) * | 2008-05-14 | 2011-07-21 | オーキッド ケミカルズ アンド ファーマシューティカルズ リミテッド | Improved production method of cefozopran |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2919112B2 (en) | 1999-07-12 |
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