CN1067074C - 碳代青霉烯类抗菌素、组合物及其制备方法 - Google Patents
碳代青霉烯类抗菌素、组合物及其制备方法 Download PDFInfo
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- CN1067074C CN1067074C CN97190911A CN97190911A CN1067074C CN 1067074 C CN1067074 C CN 1067074C CN 97190911 A CN97190911 A CN 97190911A CN 97190911 A CN97190911 A CN 97190911A CN 1067074 C CN1067074 C CN 1067074C
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- 239000002250 absorbent Substances 0.000 description 1
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- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 1
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- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
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- 229960003194 meglumine Drugs 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/887—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with a hetero atom or a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
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Abstract
本申请公开了含有稳定形式的式(Ⅰ)化合物或其药学上适用的盐、前体药物或其水合物的药用组合物，和/或者由式(Ⅰ)化合物或其药学上适用的盐、前体药物或其水合物与二氧化碳源组成的药用组合物。
Description
发明背景
本发明涉及碳代青霉烯类抗菌素组合物、该抗菌素的稳定的形式及其制备方法。该组合物可用于治疗感染的疾病，包括革兰氏阳性和革兰氏阴性、需氧菌和厌氧菌感染的疾病。本发明组合物提供了抗β-内酰胺酶良好的稳定性和满意的持续作用时间。
发明概述
本申请公开了含有式Ⅰ化合物或其药学上适用盐、稳定形式、前体药物或其水合物以及二氧化碳源的药用组合物，发明详述
这里所用的术语“稳定的形式”是指在吡咯烷的氮原子上形成有氨基甲酸基团的化合物，如式Ⅱ所示化合物。该氨基甲酸基团可通过式Ⅰ化合物或其盐、前体药物或其水合物与二氧化碳源如碳酸钠或碳酸氢钠结合得到。实例见式Ⅱ和式Ⅱ-a～Ⅱ-g。
术语“前体药物”是指这样的化合物，其在羟乙基侧链(碳代青霉烯母核6位)羟基上具有可脱去的基团、羧酸基团在碳代青霉烯母核3位上或间位羧酸基团在侧链苯环上。从本文描述中药物化学家对用于形成前体药物的基团应该是清楚的。实例有烯丙基、乙酰基、苄氧羰基、甲氧基甲基、叔丁氧基羰基、三甲基甲硅烷基等。
术语“水合物”通常意义上包括与水进行物理结合的式Ⅰ和式Ⅱ化合物。
本发明涉及含有下式碳代青霉烯类抗菌素化合物及其盐、稳定的形式、前体药物及它们的水合物的药用组合物。式Ⅰ化合物是尤其可用作静脉和肌内给药的碳代青霉烯类抗菌素。
本发明的一个方面涉及与任一药学上适用的缓冲剂配制的药用组合物，该缓冲剂在溶解时可提供pH值约6.0～约9.0。例如碳酸氢钠是优选的药学上适用的缓冲剂。在溶解时所述组合物的pH值最好为约6.2～约8.5。
另一方面，本发明包括所述化合物的稳定形式，见下面式Ⅱ。一般来讲，在溶解时能够提供二氧化碳的任一化合物可以用来与式Ⅰ化合物反应，以便得到式Ⅱ化合物。
本发明的组合物一般可以应用二氧化碳源进行配制。优选的二氧化碳源有二氧化碳(气态、液态或固态)、碳酸盐和碳酸氢盐，并优选碳酸钠和碳酸氢钠，可以将它们加到制剂中，以便在溶解时得到合适的pH，例如约6.2～8.5。式Ⅰ化合物一钠盐本身的pH约为5.4。
式Ⅰ化合物可以按美国专利No.5,478,820(Betts等，1995年12月26日颁发)进行合成，将该专利引入本申请作为参考。冷冻干燥或非冷冻干燥形式的式Ⅰ化合物与能产生二氧化碳的化合物(如碳酸钠或碳酸氢钠)反应，可将式Ⅰ化合物转变为式Ⅱ化合物。
一般来讲，将式Ⅰ化合物与二氧化碳源混合，然后使该混合物溶于合适的溶剂中，可以合成式Ⅱ化合物。可以将式Ⅰ化合物与二氧化碳源混合，并将该混合物溶解，通常可制得式Ⅱ化合物。
在众多的例子中，优选将式Ⅰ化合物与产生二氧化碳的化合物溶于含水溶剂中，然后将生成的组合物冷冻干燥，结果得到含有式Ⅱ化合物的混合物。
在溶解中式Ⅱ化合物(Ⅱ和Ⅱ-a～Ⅱ-g)溶解后转变成式Ⅰ化合物(Ⅰ,Ⅰ-a,Ⅰ-b和Ⅰ-c)。
式Ⅰ化合物可以为粉末状物，它与能产生二氧化碳的化合物混合，结果在溶解或重新组成时得到式Ⅱ化合物或其盐、前体药物或其水合物。
另外，式Ⅰ化合物与能产生二氧化碳的化合物在溶液中反应，结果生成式Ⅱ化合物，之后将该组合物进行冷冻干燥，得到含有式Ⅱ化合物或其盐、前体药物或其水合物的组合物。
在组合物中应用的碳酸钠或碳酸氢钠的量可在广泛限变内变化。例如，在制剂中碳酸钠的量可在约0.025g碳酸钠/1g药物～约/0.25g碳酸钠/1g药物范围内变化。同样，在制剂中碳酸氢钠的量可以在约/0.025g/1g药物～约0.7g/1g药物范围内变化。可以含有其他化合物，以便在稀释或重新组成时调节所述组合物的pH。例子包括氢氧化钾、氢氧化钠、N-甲基葡糖胺等。
特别有益的制剂含有约3～6份，优选约4.5份按重量计的式Ⅰ化合物或其药学上适用的盐、稳定的形式、前体药物或其水合物以及1份按重量计的碳酸氢钠。优选所述碳代青霉烯为单钠盐的形式。在上述制剂溶解时得到的pH为约6.5。按上述方式配制的药物可以延长产物在溶液中的稳定性。
特别有益的另一制剂含有约4-10份，优选约6.7份按重量计的式Ⅰ化合物或其药学上适用的盐、稳定的形式、前体药物或其水合物以及1份按重量计的碳酸钠。优选所述碳代青霉烯为单钠盐的形式。在所述制剂溶解时得到的pH为约7.5。按上述方式配制的药物可以延长产物在溶液中的稳定性。
如以上所述，式Ⅰ或式Ⅱ化合物能够以冷冻干燥或非冷冻干燥的形式应用。用一般的冷冻干燥技术制备冷冻干燥形式的产品。
其它成分也可以包括在本发明组合物中。由于所述组合物优选经注射途径给药，因此该组合物中可以包括各种稀释剂、缓冲剂、防腐剂、局部麻醉剂、张力调节剂和其他成分。
具有代表性的稀释剂的例子包括无菌注射用水、生理盐水、5％葡萄糖水溶液(D5W)、乳酸的格林氏溶液等。优选的稀释剂如生理盐水或无菌注射用水。
具有代表性的缓冲剂的例子包括磷酸盐缓中剂如磷酸二氢钠，柠檬酸盐缓冲剂如柠檬酸钠，甲葡胺和三(羟甲基)氨基甲烷。
具有代表性的防腐剂的例子包括丁基羟基丙酮(BHA)、二丁基羟基甲苯(BHT)和氯苄烷铵。
具有代表性的局部麻醉剂的例子包括苯佐卡因、利多卡因、诺法生、潘安卡因等。
具有代表性的张力调节剂的例子包括氢化钠、甘露醇、右旋糖、葡萄糖、乳糖和蔗糖。
具有代表性的药用赋形剂的例子包括水、甘露醇、山梨糖醇、右旋糖、乳糖、葡萄糖、葡聚糖、蔗糖、麦芽糖、明胶、牛血清白蛋白(BSA)、甘氨酸、甘露糖、核糖、聚乙烯吡咯烷酮(PVP)、纤维素衍生物、谷氨酰胺、肌醇、谷氨酸钾、赤藓醇、丝氨酸和其他氨基酸。
当式Ⅰ化合物与合适量的碳酸钠或碳酸氢钠配制药用组合物时，上述任一或所有的其他成分均可以包含在稀释或重新构成的制剂中。式Ⅰ化合物代表不稳定的游离酸形式。因此，本文中包括了式Ⅰ化合物的各种盐的形式，如Ⅰ-a～Ⅰ-c。 
X+代表平衡电荷的阳离子，X+的存在与化合物需要保持总的电荷呈中性有关。一般来说，该电荷的种类为形成药学上适用盐的离子如钠、钾、镁离子等。例如，当在化合物中有二个羧酸盐阴离子(如式Ⅰ-a)或相对于化合物只有二分之一摩尔量存在时(如式Ⅰ-b或Ⅰ-c)，同样也可以有二价离子(如Ca+2)存在。当平衡离子包括二价阳离子(如Ca+2)时，相对于碳代青霉烯存在的二价阳离子合适的量通常可提供总的电荷为中性。因此，二分之一摩尔量的Ca+2与单羧酸盐阴离子可以保持总的电荷呈中性。所有这些具体内容均包括在本发明中。
在Berge,S.M.等J.pharm.Sci66(1)：1～16(1977)中提到了许多形成盐的离子，将该文献列在本申请中作为参考。
以X+表示的形成盐优选的阳离子系选自钠、钾、钙和镁。
更优选的X+选自Na+、Ca+2和K+。
通过包含产生合适量二氧化碳的化合物(优选碳酸氢钠和碳酸钠)，得到下述一个或多个稳定的结构，
以上式Ⅱ化合物被看作是游离酸形式的稳定化合物。化合物Ⅱ-a～Ⅱ-g是盐形式稳定化合物例子。
包含在组合物中的产生二氧化碳化合物(如碳酸氢钠或碳酸钠)的量足以形成式Ⅱ～Ⅱ-g，并且该量任选提供在溶解或重新组成时组合物所需的pH值。
为了提供电荷平衡和使总的电荷呈中性，可以有零～3种正电荷平衡离子存在。在组合物中可以包含不同的平衡离子。因此，例如，钙和钠可以一起包含在药用组合物中，以便使总的电荷呈中性。所以所述平衡离子可以在广泛限变内变化。所述一种或多种平衡离子通常是药学上适用的阳离子。
本发明的碳代青霉烯类化合物可用于治疗动物和人的细菌感染。术语“药学上适用的盐”意指药物化学家明白的那些盐形式，即实质上是无毒的并且能提供所需药代动力学特性、可口性、吸收、分布、代谢或排泄作用的盐形式。选择盐时其他重要的因素(实质上是更实际的因素)还有原料的价格、结晶是否容易、收率、稳定性、吸湿性以及得到的批量药物的流动性。药用组合物可以方便地由有效成分与药学上适用载体制得。因此，本发明涉及药用组合物和应用碳代青霉烯类化合物治疗细菌感染的方法。
所述碳代青霉烯可用于多种药用制剂中。注射剂组合物(优选的给药途径)可以按单位剂量形式或多剂量包装进行制备。组合物可以为混悬剂、溶液剂或乳剂(实质上为油或水的)，并且可以含有各种配制剂如稀释剂、缓冲剂、防腐剂等。因此，所述化合物与上述药学适用载体一起存在于组合物中。
另外，有效成分可以为粉末状形式，在给药时将它与液体如无菌水、生理盐水等重新组成。所述粉末状可以是经冷冻干燥或非冷冻干燥的形式。
具有代表性的口服组合物通常为片剂、胶囊剂、溶液剂或混悬剂。所述组合物同样可以按单位剂量包装或按多剂量包装。在所述口服组合物中，药学上适用的载体可以包括稀释剂、制片和制颗粒助剂、润滑剂、崩解剂、缓冲剂、甜味剂、防腐剂等。
可以与药学上适用的载体一起配制成局部用药组合物，其形式为疏水或亲水软膏、霜剂、洗剂、溶液剂、涂剂或粉剂。
给药剂量很大程度上取决于需治疗的哺乳动物患者的状况和大小以及给药的途径和次数。优选非肠道途径(注射)给药。
对于供人用的组合物，不论是液体或固体，每单位剂量可以含有约0.01％～约99％活性物质，优选含有约10～60％活性物质。所述组合物通常可含有约10mg～约3000mg活性成分，但是一般来讲应用的优选剂量为约100mg～约1000mg范围。在非肠道给药中，单位剂量通常为化合物的无菌水或生理盐水溶液或为供溶解或重新组成用的粉末状形式。
式Ⅰ化合物优选的给药方法是非肠道给药的静脉(i.v)输注。另外，式Ⅰ化合物可以经肌内(i.m)注射给药。
对于成人，给予式Ⅰ抗菌化合物的剂量为每公斤体重约5～约50mg，每天1～6次。式Ⅰ化合物优选的剂量范围为约100mg～约1000mg，每天1～4次，优选每天1～2次，最好为每天1次。
更具体地说，对于轻微感染，优选的剂量为约100mg～约1000mg，每天1～4次，最好为每天1次。对于中等程度感染优选的剂量为约500～约1000mg，每天1～4次。对于威胁生命的严重感染，优选的剂量为约1000～2000mg，每天1～6次。
对于儿童，优选的剂量为5～25mg/公斤体重，每天1～4次；优选10mg/公斤体重剂量，每天1～4次。
式Ⅰ化合物是称为碳代青霉烯的广泛一类抗菌素。天然产生的碳代青霉烯类对于被称为脱氢肽酶(DHP)的肾酶的破坏是敏感的。该破坏或降解可以减弱该碳代青霉烯抗菌剂的效力。用于本发明的化合物可以明显地减少所述破坏作用，因此可以无需应用DHP抑制剂。但是，DHP抑制剂的应用是任选的，并且予计包含在本申请中。在欧洲专利申请No.79102616.4(申请日期1979年7月24日)(专利号0007614)；和No.82107174.3(申请日期1982年8月9日)(公开号0072014)中公开了DHP的抑制剂和它们与碳代青霉烯类抗菌剂一起的应用。
如果需要或必须抑制DHP，本发明化合物可以与上面专利和公开的申请中所述合适的DHP抑制剂一起合用或同时使用。所引用的欧洲专利申请确定了存在的碳代青霉烯类对DHP敏感性的测定方法，并且公开了合适的抑制剂、合并组合物以及治疗的方法。
在合并组合物中式Ⅰ化合物与DHP优选的重量比为约1∶1。优选的DHP为7-(L-2-氨基-2-羧基乙硫基)-2-(2,2-二甲基环丙烷甲酰胺)-2-庚烯酸(又称为西司他丁)或其盐。
所述碳代青霉烯对多种革兰氏阳性细菌和较少范围的革兰氏阴性细菌是有效的，因此可以用作为人用药和兽类用药。
所述组合物的药物代谢分布明显地优于相关化合物。
含有本申请所述化合物的药用组合物的典型例子见下面。
组合物1
| 化合物Ⅰ | 4.5g |
| 碳酸氢钠 | 1.0g |
将上面粉末状物成分混合。化合物Ⅰ为单钠盐形式。水溶液(225ml)的pH值约为6.5。
组合物2
| 化合物Ⅰ | 6.7g |
| 碳酸钠 | 1.0g |
将上面粉末状成分混合。化合物Ⅰ为单钠盐形式。水溶液(335ml)的pH值约为7.5。
实施例
| 化合物Ⅰ | 45.4mg/ml(相当于36mg无水的游离酸) |
| 碳酸氢钠，USP | 8.0mg/ml |
| 氯化钠，USP | 4.0mg/ml |
如上面组合物Ⅰ中所述，将粉末状成分混合，并加水(加至1.0ml)。溶液的最终pH值见下表。
在25℃测定静脉注射制剂溶液的稳定性，结果见下表。
保持在溶液中的百分比
| 浓 度(mg/ml) | 开始pH值 | 最终pH值 | 1hr | 2hrs | 4hrs | 6hrs | 8hrs | k(hr-1) | t90％(hrs) |
| 36mg/ml | 6.7 | 7.3 | 96.7 | 95.7 | 94.1 | 91.8 | 89.9 | 0.010438 | 7.3 |
| *12mg/ml | 7.0 | 7.4 | 98.6 | 98.0 | 97.2 | 96.5 | 95.0 | 0.004994 | 21.0 |
尽管这里详述了本发明某些优选的实施例，但是另外还有许多实施例属于附后本发明权利要求的范围内。因此，本发明不受上述实施例的限制。
Claims (9)
1．式Ⅱ所示化合物或其药学上适用的盐、前体药物或其水合物。
2．含有式Ⅱ化合物或其药学上适用的盐、前体药物或其水合物以及药学上适用载体的药用组合物。
3．根据权利要求1的化合物，其中药学上适用的盐系选自以下一组， 其中X+代表药学上适用的阳离子基团。
4．药用组合物，该组合物是由式Ⅰ化合物或其药学上适用的盐、前体药物或其水合物与二氧化碳源结合制得的。
5．根据权利要求4的药用组合物，其中二氧化碳源选自二氧化碳、碳酸钠和碳酸氢钠。
6．根据权利要求5的药用组合物，其中二氧化碳源为碳酸钠或碳酸氢钠。
7．使式Ⅰ碳代青霉烯或其药学上适用的盐、前体药物或其水合物稳定的方法，
8．根据权利要求7的方法，其中二氧化碳源系选自二氧化碳、碳酸钠或碳酸氢钠。
9．根据权利要求8的方法，其中二氧化碳源系选自碳酸钠和碳酸氢钠。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1851896P | 1996-05-28 | 1996-05-28 | |
| US60/018,518 | 1996-05-28 | ||
| GBGB9612668.5A GB9612668D0 (en) | 1996-06-18 | 1996-06-18 | Carbapenem antibiotic composition and method of preparation |
| GB9612668.5 | 1996-06-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101550138B (zh) * | 2008-04-03 | 2011-05-18 | 山东轩竹医药科技有限公司 | 巯基氮杂环烷酰胺醇取代的培南衍生物 |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU725298B2 (en) * | 1996-10-28 | 2000-10-12 | Merck & Co., Inc. | Stabilized carbapenem antibiotic compositions and method of making |
| US6180783B1 (en) * | 1997-06-16 | 2001-01-30 | Merck & Co., Inc. | Stabilized carbapenem intermediates and improved process for carbapenem synthesis |
| NZ500955A (en) * | 1997-06-16 | 2001-06-29 | Merck & Co Inc | Stabilized 1-beta-methyl-carbapenem intermediates and synthetic use |
| US6504027B1 (en) | 1998-03-02 | 2003-01-07 | Merck & Co., Inc. | Decarboxylation process for synthesizing carbapenem antibiotics |
| AU770165B2 (en) * | 1999-10-29 | 2004-02-12 | Merck Sharp & Dohme Corp. | Process for formulation of carbapenem antibiotic compositions |
| AR035728A1 (es) | 2001-01-16 | 2004-07-07 | Merck & Co Inc | Proceso perfeccionado para la sintesis de carbapenem |
| CN101357918B (zh) * | 2007-06-22 | 2011-05-18 | 山东轩竹医药科技有限公司 | 含有异硫脲基巯基吡咯烷的培南衍生物 |
| CN101367815B (zh) * | 2007-06-28 | 2012-07-04 | 山东轩竹医药科技有限公司 | 六元环甲酰胺取代的巯基吡咯烷碳青霉烯化合物 |
| JPWO2009075309A1 (ja) * | 2007-12-12 | 2011-04-28 | 大日本住友製薬株式会社 | 製剤組成物 |
| WO2009150630A2 (en) * | 2008-06-11 | 2009-12-17 | Ranbaxy Laboratories Limited | Process for preparing a carbapenem antibiotic composition |
| CN102365266B (zh) | 2009-03-31 | 2013-11-06 | 三菱综合材料株式会社 | 含氟n-烷基磺酰亚胺化合物及其制造方法、以及离子性化合物的制造方法 |
| WO2010151574A2 (en) | 2009-06-25 | 2010-12-29 | Shell Oil Company | Water injection systems and methods |
| US8889384B2 (en) | 2010-10-07 | 2014-11-18 | Shell Oil Company | Process for the production of alcohols from biomass |
| AU2011323322B2 (en) | 2010-11-05 | 2015-03-12 | Shell Internationale Research Maatschappij B.V. | Treating biomass to produce materials useful for biofuels |
| WO2012088108A1 (en) | 2010-12-20 | 2012-06-28 | Shell Oil Company | Process for the production of alcohols from biomass |
| BR112014013854B1 (pt) | 2011-12-15 | 2021-07-13 | Shell Internationale Research Maatschappij B.V. | Método para o tratamento de um subproduto da produção de etanol |
| IN2014DN09550A (zh) | 2012-05-17 | 2015-07-17 | Shell Int Research | |
| CN103860485A (zh) * | 2012-12-18 | 2014-06-18 | 深圳市海滨制药有限公司 | 一种厄他培南钠冻干制剂及其制备方法 |
| WO2015160887A1 (en) | 2014-04-17 | 2015-10-22 | Shell Oil Company | Processes for producing fermentation products |
| CA2954306C (en) | 2014-08-14 | 2022-08-30 | Shell Internationale Research Maatschappij B.V. | Process for preparing furfural from biomass |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079224A (zh) * | 1992-02-04 | 1993-12-08 | 曾尼卡有限公司 | 抗菌素化合物 |
Family Cites Families (2)
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| ES8502863A1 (es) * | 1982-09-10 | 1985-02-01 | Glaxo Group Ltd | Un procedimiento para la produccion de un recipiente hermeticamente cerrado que contiene al menos un antibiotico de beta-lactama. |
| CA2091309A1 (en) * | 1992-03-26 | 1993-09-27 | Frederic H. Jung | Antibiotic compounds |
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| CN101550138B (zh) * | 2008-04-03 | 2011-05-18 | 山东轩竹医药科技有限公司 | 巯基氮杂环烷酰胺醇取代的培南衍生物 |
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