CN1024754C - 抗菌冻干制剂 - Google Patents
抗菌冻干制剂 Download PDFInfo
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Abstract
一种包含摩尔比例为1∶0.7左右至7左右的作为活性成份的阿司扑克稀西林及阿司扑克稀西林的碱性盐及作为稳定剂的任意选的碱金属卤化物的抗菌冻干制剂，及一种制备该制剂的方法，所述抗菌冻干制剂能迅速溶解于蒸馏水中，而配成给患者注射用于治疗各种细菌性感染疾病的稳定溶液。
Description
本发明涉及一种新颖的抗菌冻干制剂，特别涉及一种含阿司扑克稀西林（aspoxicillin）作为活性成份的抗菌冻干制剂。
众所周知，阿司扑克稀西林（化学名称：（2S，5R，6R）-6-〔（2R）-2〔（2R）-2-氨基-3-（N-甲基氨基甲酰基）-丙酰胺基〕-2-（P-羟基苯基）乙酰氨基〕-3，3-二甲基-7-氧代-4-硫代-1-氮杂双环〔3，2，0〕庚烷-2-羧酸）对于格兰氏阴性及格兰氏阳性细菌具有强力的抗菌活性，因而作为优良的抗菌剂很有用处（参见：日本专利第二次公布（公告）第43519/1979号），而且当含有粗制的阿司扑克稀西林的水溶液用一种非极性的多孔吸附剂树脂进行提纯后并冷冻干燥，可以得到高纯质的，粉状的阿司扑克稀西林（参见：日本专利初次公布（公开）第40686/1981号）。
然而，由上述的日本专利初次公布第40686/1981号所揭示的方法得到的阿司扑克稀西林为一种非晶形的酐产物并且具有吸湿性，因而，除非贮存在防潮及避光条件下，该产品是不够稳定的。
现已发现，当上述阿司扑克稀西林在弱酸性的条件下从其水溶液中结晶出来时，可以获得一种作为药物（兼具有优良的特性，诸如堆积密度小及静态感电作用弱等）的新颖的晶状的三水合物形式的阿司扑克稀西林（参见：日本专利申请第226423/1986号），然而由此得到的阿司扑克稀西林三水合物具有较低的水溶性（即，0°时每100毫升水中溶解2.8克），因而难以用作于制备注射剂。一般地，抗菌类注射剂为了便于贮存优先考虑制备成固态，而当使用时再用合适的溶剂（例如：纯净的注射用水）进行配制。然而，由于上述的阿司扑克稀西林三水合物水溶性过低，因而，为了使用固态的制剂，在投药于病人之时，必须溶解于过大体积的溶剂中。因而由此获得的注射剂无论是用于单独注射，或者与其它注射剂进行联合输注，因为所需投药时间太长并且病人负荷过重，而不具有实用性。
另一方面，人尽所知，为了将该难溶物质溶于水中，可采用合适的方法，诸如，用冷冻干燥等合适的方法使之成为非晶形物质，从而对该物质进行改造，使之具有较大的表面积。然而，为了对阿司扑克稀西林三水合物施用这种方法，必须使之溶解于作为冷冻干燥溶剂的水中，因而，需要大量的溶剂。况且，大量的溶剂必须通过冷冻干燥而除去，而这需要大规模的设备。
本发明集中研究了不需要麻烦的处理及特殊的装置而制备阿司扑克稀西林的冷冻干燥制剂的方法，且现已发现，当一部分阿司扑克稀西林以其碱性盐的形式被使用时，游离的阿司扑克稀西林及其碱性盐的混和物能容易地被冷冻干燥而得到所要求的冻干制剂。
本发明的一个目的是提供一种含有阿司扑克稀西林作为活性组份的新颖的抗菌冷冻干燥制剂。本发明的另一个目的是提供一种易于溶解于注射用蒸馏水的阿司扑克稀西林的抗菌冻干制剂，因而适用于作为治疗各种细菌疾病的注射剂。本发明的这些目的和其它目的及优点对于那些本技术领域的技术人员可以从以下的说明书显而易见地了解到。
本发明的抗菌冻干制剂包含阿司扑克稀西林及阿司扑克稀西林的碱性盐，它们的摩尔比例为1∶0.7至1∶7左右。
因而，本发明的制剂包含一种特定比例的阿司扑克稀西林及阿司扑克稀西林的碱性盐（以下，简称为“阿司扑克稀西林盐”），既可以通过采用阿司扑克稀西林的非晶形酐，也可以通过采用如上所述的目前因较低的水溶性而造成的难以制成注射用制剂的阿司扑克稀西林三水合物。此外，本发明的制剂还具有易溶于注射用蒸馏水的优点，而且可以制
成含有高浓度的阿司扑克稀西林的注射制剂。
本发明所用的阿司扑克稀西林盐包括：例如，阿司扑克稀西林的碱金属盐类（例如，钾盐、钠盐等），碱性氨基酸盐类（例如，赖氨酸盐、精氨酸盐、鸟氨酸盐等），三羟甲氨基甲烷盐，等等。
在本发明制剂中，阿司扑克稀西林及阿司扑克稀西林盐按特定的摩尔比例被混合，即对应于1摩尔的阿司扑克稀西林配阿司扑克稀西林盐的摩尔数为0.7左右至7左右，优先采用1.5左右至7左右，特别优先采用2左右至6左右。
本发明的制剂可以任意地与作为稳定剂的碱金属卤化物（如氯化钠、氯化钾）掺合。特别优先采用的稳定剂为氯化钠。每1摩尔的整个阿司扑克稀西林及阿司扑克稀西林盐混合物中可掺合的碱金属卤化物的量优先采用0.2摩尔左右至0.7摩尔左右，特别优先采用0.4摩尔左右至0.7摩尔左右。
本发明的制剂也可以任意地与惯用的添加剂，诸如，等渗剂、麻醉剂、缓冲剂等等相混合。
本发明的制剂可以用制备普通的注射用冷冻干燥制剂的惯用方法来制备。
即采用如下方法，将阿司扑克稀西林、阿司扑克稀西林盐，及作为稳定剂的任选的碱金属卤化物及进一步加入任选的其它添加剂，溶于注射用的蒸馏水中，并且将溶液冷冻干燥而获得所需求的制剂。在该制备方法中，可以采用阿司扑克稀西林及药物学上可接受的碱性物质，以取代阿司扑克稀西林盐，而后，在它们溶解于蒸馏水中时形成了该阿司扑克稀西林盐。
在本发明中所用的阿司扑克稀西林，可处于非晶形酐及晶状的三水合物的形式。该碱性物质包括：例如，碱金属的氢氧化物（例如，氢氧化钾、氢氧化钠等等），碱金属的碳酸盐类（例如，碳酸钾、碳酸钠等等），碱金属的碳酸氢盐（例如，碳酸氢钾、碳酸氢钠等等），碱性氨基酸（例如，赖氨酸、精氨酸、鸟氨酸等等），三羟甲氨基甲烷等等。优先采用的碱性物质为氢氧化钠、氢氧化钾及碳酸钠。
当阿司扑克稀西林及阿司扑克稀西林盐被用于制备所需的制剂时，所采用的摩尔比例为，每1摩尔阿司扑克稀西林配0.7摩尔左右至7摩尔左右阿司扑克稀西林盐。在采用阿司扑克稀西林及碱性物质以制备该制剂时，每1摩尔的阿司扑克稀西林用大约0.4摩尔至0.88摩尔的碱性物质，从而当它们溶解于注射用蒸馏水中时，所形成阿司扑克稀西林盐时的量对每1摩尔的阿司扑克稀西林来说，为大约0.7摩尔至大约7摩尔。此外，在上述含量范围以内，可以制备出含有高浓度的阿司扑克稀西林的所需制剂。阿司扑克稀西林盐或碱性物质可按过量于上述的摩尔比例来使用，而在此情况下，溶解这些物质于注射用蒸馏水中后所得溶液，用一种酸，诸如盐酸、乙酸、琥珀酸、柠檬酸等，将pH调到7至7.5。
由此制得的溶液可以用惯用的方法轻易地进行冷冻干燥，例如，将溶液灌注入安瓿或小瓶中，并且在-30℃至-40℃温度下冷却进行快速冷冻，在5至70小时后，和在0.05至0.5托压力下，并提供去除潮份所需之热量时，将潮份去除。
由此而获得的本发明的抗菌冻干制剂，具有优良的贮存稳定性，及其它优点：当使用时，溶于蒸馏水中时，可以迅速溶解，不留有难溶晶体的沉淀，从而得到含有活性阿司扑克稀西林所需的浓度的所要求的稳定溶液。
在本发明中所采用的阿司扑克稀西林三水合物可以通过以下的方法制备;例如，将阿司扑克稀西林或其盐溶于一种含水溶剂（例如：水、含水低级醇、含水低级烷酮，等等），然后在弱酸性的条件下（例如：pH3-6）使之从该溶液中结晶出来。
通过以下的各实施例对本发明进行描述，但并不认为对此有任何限制。
实施例1
将1.11g阿司扑克稀西林三水合物（当转换成阿司扑克稀西林时等于1g）及0.09氢氧化钾，溶于5ml注射用的蒸馏水中，然后将溶液灌注入25ml小瓶内。将小瓶迅速冷却至-35℃，并在该温度下冷冻3小时。将所获得的产物在20-250℃的温度及0.1-0.2托的压力下干燥30小时，然后在40-50℃及0.1-0.2托压下下进一步干燥5小时，从而获得本发明所要求的抗菌冻干制剂。
如此获得的抗菌冻干制剂，含有阿司扑克稀西林及阿司扑克稀西林钾盐，它们的摩尔比例为1∶4。当5ml注射用蒸馏水加入小瓶之后，小瓶中的内容物迅速溶解，而得到含有20W/V%阿司扑克稀西林的一种透明的注射溶液（pH大约为7.5）。
实施例2至4
按与实施例1所描述过的同样的方法，不同之处在于用碱性物质代替氢氧化钾，其各自用量如表1所示，用以制备抗菌冻干制剂。
这些抗菌冻干制剂含有每1摩尔阿司扑克稀西林如表1所示摩尔量的阿司扑克稀西林盐。当把5ml注射用蒸馏水加入该抗菌冻干制剂中时，小瓶内容物迅速溶解，并得到含有20W/V%阿司扑克稀西林的透明的注射溶液。
表1
实施例 碱性物质及 制剂中所含的阿
NO. 其用量（g） 司扑克稀西林盐
（摩尔比例＊）
2 氢氧化钠 阿司扑克稀西林
（0.066） 钠盐（4）
3 三羟甲氨基甲 阿司扑克稀西林的三
烷（0.020） 羟甲氨基甲烷盐（4）
4 精氨酸 阿司扑克稀西林的
（0.028） 精氨酸盐（4）
＊制剂中每1摩尔阿司扑克稀西林的阿司扑克稀西林盐的摩尔数（以下均同）。
实施例5
将1.11g阿司扑克稀西林三水合物（当转换成阿司扑克稀西林时等于1g），0.066g氢氧化钠及0.05g氯化钠，溶于5ml注射用的蒸馏水中，并用实施例1相同的方法处理该溶液，得到所要求的抗菌冻干制剂。
如此所得的抗菌冻干制剂含有阿司扑克稀西林及阿司扑克稀西林钾盐，它们的摩尔比例为1∶4，同时还含有氯化钠，其用量为当阿司扑克稀西林及阿司扑克稀西林钠盐量之和为1摩尔时，氯化物为0.4摩尔。当5ml注射用蒸馏水加入小瓶中，小瓶的内容物迅速溶解而得到一种含20W/V%阿司扑克稀西林的透明的注射溶液（pH大约为7.5）。
实施例6至9
采用如实施例1相同的方法，不同之处在于使用其各自用量示于表2的阿司扑克稀西林三水合物及氢氧化钠，用以制备抗菌冻干制剂。
这些抗菌冻干制剂含有如该表所示摩尔比例的阿司扑克稀西林及阿司扑克稀西林钠盐。当5ml注射用蒸馏水加入该制剂时，小瓶中内容物迅速溶解，而得到透明的注射溶液，其中所含的阿司扑克稀西林的量如该表所示。（表2见文后）
ASPC：阿司扑克稀西林（Aspoxicillin）
参考例：
将50ml水加入到10g阿司扑克稀西林非晶形酐中，并在40℃下加热该混合物使之溶解，然后用稀盐酸将pH值调节至4.0。在30℃下将该混合物搅拌1小时，然后冷却至5℃。得到的沉淀物用过滤法分离，用水洗涤并进行干燥，而得到8g白色阿司扑克稀西林三水合物。
水含量（KF）：10.05%（对应于3摩尔）
阿司扑克稀西林含量（HPLC）：99.7%
旋光性〔α〕20 D：+179.5°（C＝1.0，水）
粉末X-射线衍射花样：
能源（Cu：Ni;40KV，35mA，λ＝1.5405）
距离（
） 相对强度（I）＊
15.77 w
10.77 w
9.21 vw
7.89 w
5.98 s
5.57 vs
5.34 w
4.98 vw
4.62 vs
4.39 w
4.23 m
3.97 m
3.77 vw
3.64 vw
3.54 w
3.48 w
3.37 w
3.25 m
3.13 vw
3.01 w
2.86 vw
2.81 vw
2.65 vw
2.60 vw
2.40 w
＊）相对强度（I）的标准如下所示：
vs：很强，s：强，m：中等，w：弱vw：很弱
表2
实施例 组成物数量（g） 摩尔 ASPC含量 pH
NO. ASPC Na OH 比例＊ （W/V%）
3H2O
6 0.420 0.0185 1.5 7.6 Ca.6.9
7 0.660 0.036 3 11.9 Ca.7.2
8 1.295 0.0795 5.3 23.3 Ca.7.5
9 1.955 0.125 7 35.2 Ca.7.6
ASPC：阿司扑克稀西林（Aspoxicillin）
Claims (3)
1、一种制备含有阿司扑克稀西林作为活性成份的抗菌冻干制剂的方法，其特征为，包括以下步骤：将摩尔比例为1∶0.7-7的阿司扑克稀西林及阿司扑克稀西林的碱金属盐及任选的氯化钠溶解于注射用蒸馏水中，并使该溶液冷冻干燥。
2、如权利要求1所述的方法，其特征为，其中的阿司扑克稀西林选自于由阿司扑克稀西林酐及阿司扑克稀西林三水合物组成的组。
3、如权利要求1所述的方法，其特征为，采用对应于1摩尔阿司扑克稀西林数量为0.4摩尔至0.88摩尔的一种碱金属氢氧化物代替阿司扑克稀西林的碱金属盐。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6868/87 | 1987-01-14 | ||
| JP62006868A JPS63174927A (ja) | 1987-01-14 | 1987-01-14 | 抗菌性凍結乾燥製剤 |
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| Publication Number | Publication Date |
|---|---|
| CN1034131A CN1034131A (zh) | 1989-07-26 |
| CN1024754C true CN1024754C (zh) | 1994-06-01 |
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|---|---|
| US (1) | US4966899A (zh) |
| EP (1) | EP0278243B1 (zh) |
| JP (1) | JPS63174927A (zh) |
| KR (1) | KR930001830B1 (zh) |
| CN (1) | CN1024754C (zh) |
| AT (1) | ATE61222T1 (zh) |
| AU (1) | AU597463B2 (zh) |
| CA (1) | CA1308358C (zh) |
| DE (1) | DE3861866D1 (zh) |
| DK (1) | DK15088A (zh) |
| ES (1) | ES2031930T3 (zh) |
| FI (1) | FI89454C (zh) |
| GR (1) | GR3001565T3 (zh) |
| HK (1) | HK63592A (zh) |
| HU (1) | HU197985B (zh) |
| IE (1) | IE60049B1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0367090B1 (en) * | 1988-11-01 | 1994-01-12 | Schwarz Pharma Ag | Lyophilized MDM composition and method of making it |
| EP0758651B1 (en) * | 1994-05-02 | 2002-09-11 | Shionogi & Co., Ltd. | Crystal of pyrrolidylthiocarbapenem derivative, lyophilized preparation containing said crystal, and process for producing the same |
| US8252228B1 (en) * | 2008-10-13 | 2012-08-28 | Abbott Cardiovascular Systems Inc. | Methods for sterilizing carriers for treatment of a kidney |
| CN102372727A (zh) * | 2010-08-10 | 2012-03-14 | 海南美好西林生物制药有限公司 | 一种阿扑西林钠的制备方法 |
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|---|---|---|---|---|
| US3733404A (en) * | 1970-09-04 | 1973-05-15 | Squibb & Sons Inc | Antibacterial composition containing alpha-aminobenzyl penicillins |
| US4053609A (en) * | 1975-09-12 | 1977-10-11 | Tanabe Seiyaku Co., Ltd. | Penicillins and processes for preparing the same |
| DE2623835C2 (de) * | 1976-05-28 | 1978-03-02 | C.H. Boehringer Sohn, 6507 Ingelheim | Verfahren zur Herstellung von Natriumampicillin |
| GB1539510A (en) * | 1976-08-23 | 1979-01-31 | Beecham Group Ltd | Injectable compositions |
| JPS5640686A (en) * | 1979-09-11 | 1981-04-16 | Tanabe Seiyaku Co Ltd | Purification of penicillin derivative |
| CA1242699A (en) * | 1985-02-01 | 1988-10-04 | Bristol-Myers Company | Cefbuperazone and derivatives thereof |
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- 1988-01-08 IE IE4988A patent/IE60049B1/en not_active IP Right Cessation
- 1988-01-12 CA CA000556322A patent/CA1308358C/en not_active Expired - Fee Related
- 1988-01-12 KR KR1019880000159A patent/KR930001830B1/ko not_active IP Right Cessation
- 1988-01-13 EP EP88100385A patent/EP0278243B1/en not_active Expired - Lifetime
- 1988-01-13 CN CN88100164A patent/CN1024754C/zh not_active Expired - Fee Related
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- 1988-01-13 AT AT88100385T patent/ATE61222T1/de not_active IP Right Cessation
- 1988-01-13 AU AU10226/88A patent/AU597463B2/en not_active Ceased
- 1988-01-13 ES ES198888100385T patent/ES2031930T3/es not_active Expired - Lifetime
- 1988-01-13 DK DK015088A patent/DK15088A/da not_active Application Discontinuation
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-
1991
- 1991-03-07 GR GR90400824T patent/GR3001565T3/el unknown
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1992
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Also Published As
| Publication number | Publication date |
|---|---|
| IE880049L (en) | 1988-07-14 |
| AU1022688A (en) | 1988-07-21 |
| JPH053847B2 (zh) | 1993-01-18 |
| HK63592A (en) | 1992-08-28 |
| EP0278243A1 (en) | 1988-08-17 |
| EP0278243B1 (en) | 1991-03-06 |
| FI89454B (fi) | 1993-06-30 |
| HUT46212A (en) | 1988-10-28 |
| IL85031A (en) | 1992-07-15 |
| CN1034131A (zh) | 1989-07-26 |
| AU597463B2 (en) | 1990-05-31 |
| HU197985B (en) | 1989-07-28 |
| GR3001565T3 (en) | 1992-11-23 |
| FI880027A0 (fi) | 1988-01-06 |
| SG60292G (en) | 1992-09-04 |
| FI880027A (fi) | 1988-07-15 |
| IE60049B1 (en) | 1994-05-18 |
| KR930001830B1 (ko) | 1993-03-15 |
| ES2031930T3 (es) | 1993-01-01 |
| US4966899A (en) | 1990-10-30 |
| ATE61222T1 (de) | 1991-03-15 |
| DK15088A (da) | 1988-07-15 |
| DE3861866D1 (de) | 1991-04-11 |
| FI89454C (fi) | 1993-10-11 |
| JPS63174927A (ja) | 1988-07-19 |
| DK15088D0 (da) | 1988-01-13 |
| CA1308358C (en) | 1992-10-06 |
| KR880008812A (ko) | 1988-09-13 |
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