CN102133218B - 一种头孢雷特组合物 - Google Patents
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- SLAYUXIURFNXPG-CRAIPNDOSA-N ceforanide Chemical compound NCC1=CC=CC=C1CC(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)CC(O)=O)CS[C@@H]21 SLAYUXIURFNXPG-CRAIPNDOSA-N 0.000 title claims abstract description 35
- 229960004292 ceforanide Drugs 0.000 title claims abstract description 32
- 239000000203 mixture Substances 0.000 title claims abstract description 11
- 239000004475 Arginine Substances 0.000 claims abstract description 25
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 8
- 238000002347 injection Methods 0.000 claims description 15
- 239000007924 injection Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 10
- 238000012856 packing Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000005352 clarification Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000000890 drug combination Substances 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 12
- 239000006184 cosolvent Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 235000019766 L-Lysine Nutrition 0.000 description 6
- 239000004472 Lysine Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000589516 Pseudomonas Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000588770 Proteus mirabilis Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000148131 Colibacter Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
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- 206010040047 Sepsis Diseases 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明属于医药技术领域，特别涉及到一种头孢雷特组合物，本发明的药物组合物含有：头孢雷特100-1000重量份，精氨酸20-500重量份。
Description
技术领域
本发明属于医药技术领域，特别涉及到一种头孢类抗生素头孢雷特的新的药物组合物。
背景技术
头孢雷特(ceforanide分子式C20H21N7O6S2分子量519.56 CAS登记号〖60925-61-3〗)为二代头孢，是7-氨基头孢菌酸的衍生物，在结构上与青霉素类相似。本品抗菌活性类似于头孢孟多，但对大部分革兰氏阳性菌的抑菌效果较弱，大部分大肠杆菌属、沙门氏菌、志贺氏菌属、嗜血杆菌菌属、柠檬酸菌属、亚力桑那菌属对本品敏感。临床适用于敏感菌引起的各种感染，如金葡菌(产酶和不产酶株)引起的骨和关节感染、心内膜炎，由金葡菌、肺炎链球菌、肺炎杆菌和流感杆菌引起的下呼吸道感染，由金葡菌、肺炎链球菌和大肠杆菌引起的细菌性败血症，由金葡菌、表葡菌、A型和B型链球菌、大肠杆菌、奇异变形杆菌和肺炎杆菌引起的皮肤和皮下组织感染，由大肠杆菌、奇异变形杆菌和肺炎杆菌引起的尿路感染。亦可用于外科手术预防感染。因此开发一种稳定的头孢雷特制剂具有重要意义。
1984年由美国百时美-迈瑞-施贵宝公司(Bristol-Myers-Squibb简称BMS)上市的注射用头孢雷特(商品名Precef)选用L-赖氨酸为助溶剂，但由于L-赖氨酸价格昂贵，无菌制备工艺复杂，耗用大量有机溶媒(异丙醇)，对环境有污染并可能残留到药品中，而且容易氧化，因此需要寻找一种更适合的助溶剂。
发明内容
本发明根据头孢雷特注射剂的需要，加助溶剂使其溶解于水，参考其他头孢助溶剂的添加，选用Na2CO3、NaHCO3、精氨酸，以及L-赖氨酸做助溶剂。通过实验意外的发现要使头孢雷特完全溶解，加入Na2CO3与NaHCO3后溶液颜色较深、pH值较大，加入精氨酸用量最小、颜色最浅、pH值也适中，所以选用精氨酸作为助溶剂。
因此本发明提供一种头孢雷特的新的药物组合物，该组合物含有头孢雷特和精氨酸。
本发明的药物组合物，优选的其中含有：
头孢雷特100-1000重量份
精氨酸20-500重量份
特别优选的其中含有
头孢雷特1000重量份
精氨酸400-500重量份
最优选的其中含有
头孢雷特1000重量份
精氨酸420重量份
如每1kg头孢雷特加420g精氨酸，制备成注射剂1000支。
本发明的组合物，其配制方法属于现有常规技术，如将1kg无菌头孢雷特和无菌420g精氨酸混合均匀，分装、加塞、轧盖制备成注射剂1000支，或取1kg头孢雷特，加注射用水适量搅拌使混悬，缓慢加入精氨酸420g搅拌使溶解澄清，无菌过滤，滤液冻干后分装、加塞、轧盖或滤液分装、加半塞、冻干、压塞、轧盖冻干使成注射剂1000支。
本发明的优选配方是通过以下实验筛选出来的，实验如下：
实验方法：
考虑本品配置制剂、注射剂的需要，需加助溶剂使其溶解于水，参考其他头孢助溶剂的添加，拟分别用Na2CO3、NaHCO3、精氨酸，以及L-赖氨酸做助溶剂，并作为比对，确定使用哪种作为助溶剂，拟定浓度为100mg/ml，加入助溶剂后溶液应澄清透明，如显色，与标准比色液(中国药典2010年版附录IX A第一法)比较。
实验材料：
(1)头孢雷特样品 河南中帅医药科技发展有限公司制备
批号 20100703
(2)仪器 PHS-20C数字式酸度计，美国奥豪斯AR2140分析天平，
中国药典标准比色液
(3)试剂碳酸钠，碳酸氢钠，精氨酸，L-赖氨酸
实验步骤
精密称定4份头孢雷特原料，分别加入Na2CO3、NaHCO3、精氨酸、L-赖氨酸适量搅拌使其完全溶解，记录加入量，并测定其pH值，并与黄色标准比色液或黄绿色标准比色液比对。
(1)NaCO3 头孢雷特
完全溶解并显黄棕色
加入量663.1mg 与黄色8号标准比色液对比 大于10号
PH值为9.86
(2)加入NaHCO3 头孢雷特
完全溶解并显黄棕色
加入量424.6mg 与黄色8号标准比色液对比 大于10号
PH值为8.17
(3)加入精氨酸 头孢雷特
完全溶解并显黄色
加入量180.6mg 与黄色8号标准比色液对比 小于8号
PH值为7.58
(4)加入L-赖氨酸 头孢雷特
完全溶解并显黄色
加入量218.6mg 与黄色8号标准比色液对比 小于8号
PH值为7.88
实验结果
由以上实验可知，Na2CO3与NaHCO3加入量较多且颜色较深，pH值较大，精氨酸加入量最少，且颜色最浅，pH值也最为适宜人体pH。
所以选用精氨酸作为助溶剂，加入量定为每1kg头孢雷特加420g精氨酸。
具体实施方式
以下通过实施例，进一步说明本发明，但不作为对本发明的限制。
实施例1
本发明的注射剂其配方组成如下：
无菌头孢雷特 1000g
无菌精氨酸 420g
制成 1000支
制备工艺
相关药品类别GMP条件下，将无菌头孢雷特和无菌精氨酸混合均匀，分装；加塞，轧盖制备成供注射用药品。
实施例2
本发明的注射剂其配方组成如下：
冻干无菌粉的组方如下：
头孢雷特 1000g
精氨酸 420g
制成 1000支
制备工艺：取处方量的头孢雷特，加注射用水适量使混悬，缓慢加入精氨酸使溶解澄清，相关药品类别GMP条件下无菌(0.22μm微孔滤膜)过滤，滤液冻干后分装或分装后冻干使成注射用无菌混合物。
Claims (5)
1.一种头孢雷特药物组合物，其特征在于，该组合物含有：
头孢雷特1000重量份，
精氨酸420重量份。
2.根据权利要求1的药物组合物，其特征在于，每1kg头孢雷特加入420g精氨酸，制备成注射剂1000支。
3.根据权利要求1的药物组合物，其特征在于，必要时加入注射剂所需要的辅料。
4.权利要求1的药物组合物的制备方法，其特征在于，
注射剂其配方组成如下：
制备工艺：在相关药品类别GMP条件下，将无菌头孢雷特和无菌精氨酸混合均匀，分装，加塞，轧盖制备成供注射用药品。
5.权利要求1的药物组合物的制备方法，其特征在于，
冻干无菌粉的组方如下：
制备工艺：取处方量的头孢雷特，加注射用水适量使混悬，缓慢加入精氨酸使溶解澄清，在相关药品类别GMP条件下除菌过滤，滤液冻干后分装或分装后冻干成注射用无菌混合物。
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| CN1419450A (zh) * | 2000-01-26 | 2003-05-21 | 尼科克斯公司 | 抗微生物药物的硝酸盐 |
| WO2005009948A2 (en) * | 2002-08-29 | 2005-02-03 | Baylor College Of Medicine | Peptide inhibitors of beta-lactamases |
| WO2007067779A2 (en) * | 2005-12-08 | 2007-06-14 | Tsrl, Inc. | Methods and compositions for drug delivery enhancement |
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| CN1419450A (zh) * | 2000-01-26 | 2003-05-21 | 尼科克斯公司 | 抗微生物药物的硝酸盐 |
| WO2005009948A2 (en) * | 2002-08-29 | 2005-02-03 | Baylor College Of Medicine | Peptide inhibitors of beta-lactamases |
| WO2007067779A2 (en) * | 2005-12-08 | 2007-06-14 | Tsrl, Inc. | Methods and compositions for drug delivery enhancement |
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