CN1010551B - 含抗菌氨基糖甙类的复方注射剂制备工艺 - Google Patents
含抗菌氨基糖甙类的复方注射剂制备工艺Info
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Abstract
本发明提出制备色泽和pH稳定的非经肠给药注射药剂的工艺过程。该药剂含有氨基糖甙类抗生素,该抗生素结构中有4′和5′间的不饱和键和5′位氨烷基取代的吡喃糖环,较佳者为西梭霉素,乙基西梭霉素或5-表西梭霉素或其非经肠给药可接受的盐类。根据本发明的工艺,活性组份或其盐类溶解于水,调节其pH值为7.3~7.4,加入抗氧化剂,通入氮气过滤,灭菌,然后灌入安瓿。
Description
本发明是关于pH和色泽稳定的非经肠给药复方注射剂的制备工艺。该复方含有在4′和5′位之间为不饱和键,并在5′位有氨烷基取代的吡喃糖环的抗菌的氨基糖甙类,较佳者为西梭霉素(sisomicine),乙基西梭霉素(Netylmicine)或5-表西梭霉素,或其非经肠给药可接受的盐类。制备工艺为:将活性组份或其盐类的水溶液的pH值调节到7.3~7.4之间,加入抗氧化剂,通入氮气,过滤后灭菌,在氮气流和无菌条件下灌入安瓿。
已知上述氨基糖甙类抗生素存在着某些与pH和色泽稳定性有关的问题,为了解决这些问题,匈牙利专利申请书NO.SchE-699提出,将复合物pH值调节到5.0~6.5,最好(但不是必需)加入抗氧化剂。根据该专利,制备稳定注射复方的最佳条件是使其pH值为6.2~6.5。
在研究西梭霉素硫酸盐的不同pH时电化学氧化时发现,随着pH值增大电化学氧化最高电位降低至某一限度。图1,2和3表示西梭霉素硫酸盐作为活性组份,其成份与实例1相同的注射复方电化学氧化时所得的电位值曲线。
曲线表明,pH值较高的注射液最大电位值较小。出乎意料地发现,虽然最大电位值随着pH值增高而降低,调节到较高pH值(pH=7.3)的西梭霉素注射复方却比pH值较低的要稳定。由上述其它抗生素组成的注射复方也是如此。
本发明的理论基础是:从上述抗生素制备稳定的注射复方,应使其pH值比以前记载的要高。
正常血液或血浆,亦即生理血液和组织的pH值范围为7.3~7.4,本研究工作采用同样的pH值范围。于是,抗生素可在最适宜的pH条件下,即在生理血液的pH下被摄入生物体,从而可以避免从治疗观点看是不必要的作用影响生物体。
根据本发明,含有活性成份西梭霉素(匈牙利专利说明书No.079,145),乙基西梭霉素(匈牙利专利说明书Mo.170,513)或其类似抗生素、或其有关衍生物的稳定的药剂复方可被制备。
亚磷酸盐或亚硫酸盐可优先选用作抗氧化剂,但任何其它中性或对有机体无害的物系也可用作抗氧化剂。
可加入氢氧化钠和/或缓冲剂调节pH值。下列缓冲剂可优先选用:2-氨基-2-(羟甲基)-1,3-丙二醇缓冲剂,氢氧化钠+磷酸氢钾缓冲剂。
本发明可用下述实例(但不仅限于这些实例)说明:
实施例1
进行以下对比实验,其中
-未调节pH值的西梭霉素硫酸盐溶液(1a),
-匈牙利专利申请书NO.SchE-699叙述的,认为是最佳的pH=6.2溶液(1b),以及
-按照本发明制备的溶液(1c)
上述三种溶液进行稳定性的比较。
溶液的组成(1毫升溶液中的含量)和制备方式如下
1a)
西梭霉素
(以西梭霉素硫酸盐形式) 50.0毫克
甲基亚硫酸氢钠
(Sodium methabisulphite) 3.0毫克
对羟基苯甲酸甲酯 0.8毫克
对羟基苯甲酸丙酯 0.1毫克
乙二胺四乙酸二钠 0.1毫克
氯化钠 3.6毫克
蒸馏水 加至1.0毫升
1b)
西梭霉素(以西梭霉素硫酸盐形式) 50.0毫克
亚硫酸钠 0.8毫克
甲基亚硫酸氢钠 2.4毫克
对羟基苯甲酸丙酯 0.1毫克
对羟基苯甲酸甲酯 0.8毫克
乙二胺四乙酸二钠 0.1毫克
氯化钠 3.9毫克
蒸馏水 加至1.0毫升
上述溶液的pH值约为5.2,加入0.1N氢氧化钠溶液,调节其pH值为6.2。
1c)
西梭霉素(以西梭霉素硫酸盐形式) 50.0毫克
亚硫酸钠 0.8毫克
甲基亚硫酸氢钠 2.4毫克
对羟基苯甲酸丙酯 0.1毫克
对羟基苯甲酸甲酯 0.8毫克
乙二胺四乙酸二钠 0.1毫克
氯化钠 3.9毫克
蒸馏水 加至 1.0毫升
所得溶液pH值约为5.2,加入1N氢氧化钠溶液调节其pH值为7.35。将所制得溶液在氮气下装灌。
将上述三种溶液以下法进行稳定性试验:
将测试品在空气恒温箱中于40°,50°和60℃处理30天,然后测定其pH值,色泽和活性组份含量。色泽根据匈牙利药典第六版(Ph.Hg.VI)方法,与色标比较而测定;用微生物方法测定其生理活性来检测活性组份含量。所得数据列于表1。
从表1可见,测试品1a不耐热,1b的活性组份含量在热处理后无变化,但是其色泽即使经40℃处理也会显著变深;同时其pH值显著降低,在1c的情况下,即使经60℃处理,色泽和含量均在合格范围内,pH值保持不变。
实施例2
含有以下列组分的药剂的制备:
西梭霉素(以硫酸盐形式) 10.0毫克
对羟基苯甲酸丙酯(Ph.Hg.VI) 0.2毫克
对羟基苯甲酸甲酯(Ph.Hg.VI) 1.3毫克
乙二胺四乙酸二钠(BP.73) 0.1毫克
亚硫酸钠(BP.80) 1.5毫克
焦亚硫酸钠(Ph.Hg.VI) 2.5毫克
氯化钠(Ph.Hg.VI) 4.9毫克
注射用蒸馏水(Ph.Hg.VI) 加至1.0毫升
所得溶液pH值为5.95,加入2-氨基-2-(羟甲基)-1,3-丙二醇缓冲液使其pH为7.4,通入氮气,所得溶液在无菌条件下用细菌漏斗过滤后,在氮气下灌入安瓿。
上述溶液的色泽、pH和活性成份的稳定性与实例1的1c相当。
实施例3
按照实施例2制备含有下列组分的药剂:
乙基西梭霉素碱(以硫酸盐形式) 50.0毫克
对羟基苯甲酸丙酯(Ph.Hg.VI) 0.1毫克
对羟基苯甲酸甲酯(Ph.Hg.VI) 0.8毫克
乙二胺四乙酸二钠(BP.73) 0.1毫克
焦亚硫酸钠(Ph.Hg.VI) 3.0毫克
亚硫酸钠(BP.80) 4.0毫克
氯化钠(Ph.Hg.VI) 2.0毫克
注射用蒸馏水 加至1.0毫升
在上述溶液中加入氢氧化钠+硫酸氢钾缓冲液使原pH值由6.2变为7.3,然后按实例2方法制成安瓿剂。
将该溶液在40°,50°和60℃处理30天,其色泽,pH和活性组份的稳定性均为满意。
表1
1a 1b 1c
40℃ 50℃ 60℃ 40℃ 50℃ 60℃ 40℃ 50℃ 60℃
pH 2.25 2.38 2.38 3.39 3.39 2.42 7.30 7.30 7.30
色泽 S5S6~7S6~7S4S6~7S6~7S0~1S2S2
活性组份
93.9 90.6 79.0 99.0 99.5 99.0 99.7 99.7 99.6
含量
Claims (3)
1、制备pH和色泽稳定的非肠道给药注射制剂的方法,该方法特征为:
a.将作为活性成分的西棱霉素或乙基西棱霉素或它们的非肠道给药的药用盐溶于水,
b.调节该溶液的pH至7.3-7.4,
c.往b)溶液中加入抗氧化剂,
d.灭菌过滤后往c)溶液中通入氮气,
e.在氮气下将该溶液装入安瓿。
2、根据权利要求1的方法,其特征为:用亚磷酸钠或亚硫酸钠作为抗氧化剂。
3、根据权利要求1或2的方法,其特征为:用包括2-氨基-2-(羟甲基)1,3-丙二醇的缓冲体系来调节溶液的pH。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU85859A HU197514B (en) | 1985-03-07 | 1985-03-07 | Process for production of injection sulution containing acid-additional salts od sysomicin |
HU859/85 | 1985-03-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN85106763A CN85106763A (zh) | 1987-02-11 |
CN1010551B true CN1010551B (zh) | 1990-11-28 |
Family
ID=10951729
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN85106763A Expired CN1010551B (zh) | 1985-03-07 | 1985-09-09 | 含抗菌氨基糖甙类的复方注射剂制备工艺 |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP0195114B1 (zh) |
JP (1) | JPS61267523A (zh) |
CN (1) | CN1010551B (zh) |
AU (1) | AU587014B2 (zh) |
BE (1) | BE904289A (zh) |
CA (1) | CA1267091A (zh) |
DD (1) | DD243208A5 (zh) |
DE (1) | DE3577657D1 (zh) |
DK (1) | DK165669C (zh) |
ES (1) | ES8704078A1 (zh) |
GB (1) | GB2171907B (zh) |
GR (1) | GR851869B (zh) |
HU (1) | HU197514B (zh) |
IL (1) | IL77958A0 (zh) |
IT (1) | IT1203543B (zh) |
LU (1) | LU86343A1 (zh) |
NL (1) | NL8600480A (zh) |
PT (1) | PT82144B (zh) |
SE (1) | SE466384B (zh) |
SU (1) | SU1440328A3 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115671044A (zh) * | 2022-11-29 | 2023-02-03 | 江苏四环生物制药有限公司 | 一种硫酸奈替米星注射液及其制备方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3962429A (en) * | 1973-08-01 | 1976-06-08 | Chugai Seiyaku Kabushiki Kaisha | Method for reducing side effects of aminoglycoside antibiotics and composition therefor |
DE2726208A1 (de) * | 1977-06-10 | 1978-12-21 | Bayer Ag | 1-n-formylsisomicin, verfahren zu seiner herstellung sowie seine verwendung als arzneimittel |
US4327087A (en) * | 1978-01-16 | 1982-04-27 | Schering Corporation | Stabilized Netilmicin formulations |
US4223022A (en) * | 1978-01-16 | 1980-09-16 | Schering Corporation | Stabilized aminoglycoside antibiotic formulations |
-
1985
- 1985-03-07 HU HU85859A patent/HU197514B/hu not_active IP Right Cessation
- 1985-07-29 GR GR851869A patent/GR851869B/el unknown
- 1985-07-31 DE DE8585109621T patent/DE3577657D1/de not_active Expired - Fee Related
- 1985-07-31 EP EP85109621A patent/EP0195114B1/en not_active Expired - Lifetime
- 1985-09-09 CN CN85106763A patent/CN1010551B/zh not_active Expired
-
1986
- 1986-02-20 AU AU53845/86A patent/AU587014B2/en not_active Ceased
- 1986-02-21 DD DD86287250A patent/DD243208A5/de unknown
- 1986-02-21 IL IL77958A patent/IL77958A0/xx not_active IP Right Cessation
- 1986-02-26 NL NL8600480A patent/NL8600480A/nl not_active Application Discontinuation
- 1986-02-26 BE BE0/216317A patent/BE904289A/fr not_active IP Right Cessation
- 1986-03-04 IT IT67172/86A patent/IT1203543B/it active
- 1986-03-05 PT PT82144A patent/PT82144B/pt unknown
- 1986-03-06 DK DK101786A patent/DK165669C/da not_active IP Right Cessation
- 1986-03-06 CA CA000503435A patent/CA1267091A/en not_active Expired - Lifetime
- 1986-03-06 SE SE8601050A patent/SE466384B/sv not_active IP Right Cessation
- 1986-03-06 ES ES552709A patent/ES8704078A1/es not_active Expired
- 1986-03-06 LU LU86343A patent/LU86343A1/de unknown
- 1986-03-06 JP JP61049489A patent/JPS61267523A/ja active Granted
- 1986-03-07 SU SU864027095A patent/SU1440328A3/ru active
- 1986-03-07 GB GB8605629A patent/GB2171907B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
IT1203543B (it) | 1989-02-15 |
EP0195114B1 (en) | 1990-05-16 |
BE904289A (fr) | 1986-06-16 |
EP0195114A2 (en) | 1986-09-24 |
SE466384B (sv) | 1992-02-10 |
EP0195114A3 (en) | 1988-02-03 |
NL8600480A (nl) | 1986-10-01 |
LU86343A1 (fr) | 1986-06-24 |
SE8601050D0 (sv) | 1986-03-06 |
HUT40758A (en) | 1987-02-27 |
ES552709A0 (es) | 1987-04-01 |
PT82144A (en) | 1986-04-01 |
DK101786D0 (da) | 1986-03-06 |
DK101786A (da) | 1986-09-08 |
DD243208A5 (de) | 1987-02-25 |
IT8667172A0 (it) | 1986-03-04 |
AU5384586A (en) | 1986-09-11 |
IL77958A0 (en) | 1986-08-31 |
DE3577657D1 (de) | 1990-06-21 |
JPS61267523A (ja) | 1986-11-27 |
PT82144B (pt) | 1988-02-17 |
SU1440328A3 (ru) | 1988-11-23 |
DK165669B (da) | 1993-01-04 |
GB8605629D0 (en) | 1986-04-16 |
JPH0572365B2 (zh) | 1993-10-12 |
DK165669C (da) | 1993-06-14 |
SE8601050L (sv) | 1986-09-08 |
AU587014B2 (en) | 1989-08-03 |
GB2171907B (en) | 1989-06-14 |
HU197514B (en) | 1989-04-28 |
CN85106763A (zh) | 1987-02-11 |
GB2171907A (en) | 1986-09-10 |
ES8704078A1 (es) | 1987-04-01 |
GR851869B (zh) | 1985-12-02 |
CA1267091A (en) | 1990-03-27 |
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