CN1374857A - 肠胃外用磷雌氮芥和磺烷基醚环化糊精制剂 - Google Patents
肠胃外用磷雌氮芥和磺烷基醚环化糊精制剂 Download PDFInfo
- Publication number
- CN1374857A CN1374857A CN00812947A CN00812947A CN1374857A CN 1374857 A CN1374857 A CN 1374857A CN 00812947 A CN00812947 A CN 00812947A CN 00812947 A CN00812947 A CN 00812947A CN 1374857 A CN1374857 A CN 1374857A
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- CN
- China
- Prior art keywords
- estramustine phosphate
- preparation
- sulfoalkyl ether
- dextrin
- formulations
- 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.)
- Pending
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- 229960004750 estramustine phosphate Drugs 0.000 title claims abstract description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 239000000203 mixture Substances 0.000 title claims abstract description 17
- 238000009472 formulation Methods 0.000 title claims abstract description 16
- -1 sulfoalkyl ether Chemical compound 0.000 title claims description 35
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- 239000003814 drug Substances 0.000 claims description 22
- 238000001990 intravenous administration Methods 0.000 claims description 17
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- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 16
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
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- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 claims description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Epidemiology (AREA)
- Organic Chemistry (AREA)
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- Pulmonology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
一种药物制剂,其包含肠胃外可接受的载体或稀释剂,磷雌氮芥和磺烷基醚环化糊精。根据一种联合化疗方案,该制剂能够与一种或多种化学治疗剂联合用药。该制剂使磷雌氮芥的给药不会在注射部位产生副作用。
Description
技术领域
本发明涉及肠胃外用磷雌氮芥(estramustine phosphate)药物制剂，具体涉及还包含磺烷基醚环化糊精(sulfoalkyl ether cyclodextrins)在内的肠胃外用磷雌氮芥药物制剂。
背景技术
磷雌氮芥(The Merck Index，XII Ed.，No.3749，1996)是一种雌二醇-17β-磷酸衍生物，在本领域内是广为人知的抗肿瘤剂，目前用于治疗晚期前列腺腺癌。
该药通常口服给药，优选剂量是10-15mg/kg/天。然而在一些特定的病例中也采用静脉内给药。
例如，已报道磷雌氮芥在初始的静脉内给药后口服给药，剂量与口服该药的剂量相同，也就是每天静脉内给药300-600mg，通常在连续数天内重复给药(参见英国泌尿学杂志(British Journal of Urology)，1977，49，73-79；泌尿学杂志(J.Urol)108：303-306，1972；欧洲临床药理学(Eur.Clin.Pharmacol.)26(1)，113-119，1984；Eur、Urol.1990，17，216-218)。
已知磷雌氮芥和其它用于抗肿瘤治疗的广为人知的细胞毒化合物在肠胃外给药，尤其是静脉内给药时，能够引起或者可能引起注射部位的血管损伤。
例如，对以剂量300mg/天缓慢静脉内注射或者大丸剂(bolus)给药磷雌氮芥治疗患者的研究表明，在外周静脉注射部位发生了血栓性静脉炎和局部刺激。
这些缺点被认为是静脉内给药磷雌氮芥的主要局限，因此在许多患者中需要建立中心线(central line)给药，或者在一些病例中甚至中断治疗。
为了使不希望出现的细胞毒性剂静脉内给药相关效应降低到最少，本领域报道了几种方法。
其中的一种方法是在制备已知能够引起溃疡性损伤的细胞毒药物的肠胃外给药制剂时使用羟丙基环化糊精。参见Supergen Inc.名义下的美国专利5,804,568。
已知磺烷基醚环化糊精在本领域内用做不溶解或低溶解度药物的增溶剂(参见Kansas大学名义下的US5,134,127)。
在这点上，我们发现包含磷雌氮芥和磺烷基醚环化糊精的肠胃外使用制剂出乎意料地获得了对抗给药雌莫司汀相关副作用的最佳保护。
发明公开
因此包含与磺烷基醚环化糊精混合的磷雌氮芥的肠胃外用制剂是本发明的目的。
一旦给患者静脉内给药后，本发明的目的制剂在注射部位不会引起溃疡性损伤，也不会引起血栓性静脉炎。
在本发明中，除非另外指明，术语包含活性成分磷雌氮芥的制剂是指任何包含磷雌氮芥的制剂，其中磷雌氮芥是酸形式的或作为肠胃外给药的可药用盐，例如与碱性氨基酸或N-甲基葡萄糖胺(或称为甲基葡胺)形成的盐。
优选的磷雌氮芥是它的甲基葡胺盐形式。
术语磺烷基醚环化糊精是任意的上述类型的环化糊精，其中烷基表示直链或支链C1-C6烷基基团，例如甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，正己基和类似基团。
本发明的优选制剂包含与磺丁基醚β-环化糊精混合的磷雌氮芥。
根据本发明的优选实施方案，上述制剂有利地用于静脉内给药。
同样地，本发明的这些制剂能够以缓慢注射的方式对患者给药，例如在约30分钟到约3小时的时间内给药，或者以大丸剂注射的方式也就是IV(静脉内)推注方式给药。
优选地，这些制剂包含与磺烷基醚环化糊精混合的磷雌氮芥，其中，磷雌氮芥和磺烷基醚环化糊精的重量比分别是从大约1∶1到大约1∶5。
但是，相对于活性成分而言，含有即使更大量磺烷基醚环化糊精的制剂仍然有效，因此也包括在本发明的范围内。
此外，即使在需要高剂量活性成分的时候，本发明也提供了静脉内给药磷雌氮芥的非常有利的方法。
因此本发明的另一目的是包含与磺烷基醚环化糊精混合的磷雌氮芥的肠胃外用制剂，其中单个输注剂量超过1300mg的活性成分。
根据本发明另外一个优选的实施方案，提供了包含与磺烷基醚环化糊精混合的磷雌氮芥的肠胃外用制剂，其中单个输注剂量超过950mg/m2的活性成分。
在一个更进一步的优选实施方案中，提供了冻干形式的磷雌氮芥，并且磺烷基醚环化糊精处于生理溶液中。该型制剂典型地能够以试剂盒形式提供。
本发明的目的制剂允许活性成分以单一药物的形式给药，也可以与已知的抗肿瘤治疗如放疗或化疗方案相结合，与下列药物联合给药：细胞生长抑制剂或细胞毒药物，抗生素类药物，烷化剂，抗代谢药物，激素药物如芳香酶(aromatase)抑制剂，免疫学药物，干扰素类药物，环加氧酶抑制剂(如COX-2抑制剂)，金属基质蛋白酶(metallomatrixprotease)抑制剂，端粒酶抑制剂，酪氨酸激酶抑制剂，抗生长因子受体药物，抗-HER药物，抗-EGFR药物，抗血管生成药物，法尼基转移酶抑制剂，ras-raf信号转导途径抑制剂，细胞周期抑制剂，其它cdks抑制剂，微管蛋白结合剂，拓扑异构酶I抑制剂，拓扑异构酶II抑制剂以及类似药物。
例如，上述制剂能够与一种或多种化学治疗剂任选在其脂质体制剂内联合给药。
化学治疗剂的例子是例如紫杉烷(taxane)，紫杉烷衍生物，CPT-11，喜树碱及其衍生物，蒽环类药的糖苷(anthracycline glycosides)如多柔比星，伊达比星或表柔比星，依托泊苷，诺威本，长春碱，卡铂，顺铂以及类似药物，可任意选择在其脂质体制剂之内。
此外，上述制剂也可以与蛋白激酶抑制剂联合给药，如Sugen公开的吲哚满酮衍生物，公开于国际专利申请WO96/40116和WO99/61422，它们在此引入本文作为参考。
在这点上，本发明的目的制剂优选与3-[4-(2-羟基乙基-3，5-二甲基吡咯-2-基)methylidenyl]-2-吲哚满酮和3[(2，4-二甲基吡咯-5-基)methylidenyl]-2-吲哚满酮，更常见的称法分别是Sugen SU 6668和SU 5416。
本发明的制剂在联合形式的制剂不合适时可以与已知的抗癌剂相继给药。
因此，本发明的另一个目的是含有与磺烷基醚环化糊精混合的磷雌氮芥的肠胃外用制剂和一种或多种化学治疗剂的产品，作为抗癌治疗中同时、分开或相继使用的联合制品。毒理学
为了研究与本发明的磷雌氮芥制剂相比较，大鼠静脉重复给药后磷雌氮芥的局部刺激效应，将此活性成分溶解于不同的载体，如用于注射的水溶液和用于注射并另含有不同量磺烷基醚环化糊精的水溶液。
具体地，制备和试验了下列磷雌氮芥∶磺丁基醚β-环化糊精重量比分别为1∶2和1∶4的溶液。
研究使用了雄性Sprague-Dawley大鼠，因为它们可以预测人的中毒变化。在研究开始时大鼠为6周龄。
在3天的时间里，多组大鼠静脉内重复给药甲葡胺盐形式的磷雌氮芥。然后在第四和第五天分别杀死一半大鼠。
在检测的所有不同溶液中，磷雌氮芥的剂量水平均是150mg/kg/天。
每天记录临床观察结果。在治疗期间，血栓性静脉炎副作用导致尾巴有暗蓝/黑色着色。
一个基于尾巴着色及其扩展的评分系统用于评估不同的检测制剂。该评分系统将磷雌氮芥水溶液作为阳性对照(也就是明显中毒)。向对照组给予注射用水作为阴性对照(也就是没有中毒迹象)。对用本发明不同制剂处理的大鼠的尾巴进行了组织学检测。水溶液中的磷雌氮芥在所使用的剂量下经首次给药后诱导了注射部位的局部刺激效果，在实验的最后引起了明显的中毒迹象。
根据本发明，含有磺丁基醚β-环化糊精的制剂即使在该赋形剂处于低浓度时也没有显示中毒迹象。用含磺丁基醚β-环化糊精制剂处理的大鼠的尾组织学评估在与对照组的尾比较时没有显示任何损伤。
因此结论认为，本发明含有磺烷基醚环化糊精的水溶液中的磷雌氮芥在与磷雌氮芥水溶液相比较时诱导的局部刺激明显更少。
一个特别优选的本发明磷雌氮芥制剂给药方案是每周一次单剂输注最大剂量达4000mg或3500mg/m2。另外一个优选的给药方案是每2周到4周单剂输入药物一次。在考虑到其它可选的伴随治疗时，一种方案可能优于另一种。这些方案可以通过连续或重复的方式重复。
本发明的制剂可以用于抗肿瘤治疗，尤其是治疗前列腺癌，乳腺癌，黑素瘤，肺癌，胰腺癌，结肠直肠癌，卵巢癌和脑癌。
本发明的目的制剂是根据在肠胃外用药物形式制备中采取的传统技术制备的。典型地，将适量的磷雌氮芥以干粉的形式或者冻干形式溶于肠胃外用的可药用溶液中，然后与适量的磺烷基醚环化糊精如磺丁基醚β-环化糊精混合。
例如，适量的磷雌氮芥以适当的盐如N-甲基葡萄糖胺盐的形式溶于适量的无菌水或葡萄糖水溶液(如静脉内给药用5％的葡萄糖水溶液)中，然后与适量的磺丁基醚β-环化糊精粉末混合。
然后根据传统技术搅动并消毒上述混合液，随后冻干。
制备冻干制剂并储存在小瓶中用于注射；加入适量的肠胃外用无菌水或生理溶液后，制备的最终制剂可以用于注射。
或者，也可以用已经含有适量的磺烷基醚环化糊精的适量肠胃外用无菌水或生理溶液重溶含有所述有效成分的冻干制剂制备注射用的最终制剂。
上述方法也适用于制备高剂量的磷雌氮芥制剂，同时保持各成分间具有理想的重量比。
注射用制剂的单位强度依赖于溶液中活性成分本身的浓度，当然也依赖于用于制备最终制剂的小瓶容积。
此外，本发明的制剂可以任选含有肠胃外用的可药用赋形剂，例如膨胀剂，如乳糖或甘露醇，pH缓冲剂，抗氧化剂，防腐剂，张力调节剂以及类似物质。
下列例子是为了更好地说明本发明，对本发明没有任何限制。
实施例1制备重量比为1∶4.2的磷雌氮芥∶磺丁基醚β-环化糊精
在烧杯中称量300mg的磷雌氮芥，然后用磁力搅拌的方法使它分散于5ml的水中。在搅拌的情况下将120.8mg的N-甲基葡萄糖胺加入到活性成分的水分散物中，数分钟后，得到了澄清的溶液。加入1250mg的磺丁基醚β-环化糊精，搅拌溶液直到完全溶解。
在获得的溶液中加水直到终体积为10ml，这样磷雌氮芥和磺丁基醚β-环化糊精的终浓度分别达到30mg/ml和125mg/ml(重量比1∶4.2-摩尔比1∶1)。
上述方法制备的溶液经适当的过滤灭菌后在大鼠中检测其局部静脉耐受性。
实施例2
在实施例1中描述的制剂也可以通过将含有300mg/小瓶活性成分的商品化Estracyt冻干制剂溶解来制备。用10ml浓度为125mg/ml的磺丁基醚β-环化糊精重溶该制剂以使磷雌氮芥和磺丁基醚β-环化糊精的终浓度分别达到30mg/ml和125mg/ml(重量比1∶4.2-摩尔比1∶1)。
实施例3制备重量比为1∶2.1的磷雌氮芥∶磺丁基醚β-环化糊精
在烧杯中称量300mg的磷雌氮芥，然后用磁力搅拌的方法使它分散于5ml的水中。在搅拌的情况下将120.8mg的N-甲基葡萄糖胺加入到活性成分的水分散物中，数分钟后，得到了澄清的溶液。加入625mg的磺丁基醚β-环化糊精，搅拌溶液直到完全溶解。
在获得的溶液中加水直到终体积为10ml，这样磷雌氮芥和磺丁基醚β-环化糊精的终浓度分别达到30mg/ml和62.5mg/ml(重量比1∶2.1-摩尔比1∶0.5)。
上述方法制备的溶液经适当的过滤灭菌后在大鼠中检测其局部静脉耐受性。
实施例4
在实施例3中描述的制剂也可以通过将含有300mg/小瓶活性成分的商品化Estracyt冻干制剂溶解来制备。用10ml浓度为62.5mg/ml的磺丁基醚β-环化糊精重溶该制剂以使磷雌氮芥和磺丁基醚β-环化糊精的终浓度分别达到30mg/ml和62.5mg/ml(重量比1∶2.1-摩尔比1∶0.5)。
Claims (23)
1.一种药物制剂，包含肠胃外可接受的载体或稀释剂，以及磷雌氮芥和磺烷基醚环化糊精。
2.根据权利要求1的制剂，其中磷雌氮芥和磺烷基醚环化糊精的重量比是大约1∶1到大约1∶5。
3.根据权利要求1或2的制剂，其采用含有至少1300mg磷雌氮芥的单个输注剂量形式。
4.根据前述任何一项权利要求的制剂，其采用含有至少950mg/m2磷雌氮芥的单个输注剂量形式。
5.根据前述任何一项权利要求的制剂，其中磺烷基醚环化糊精是直链或支链C1-C6磺烷基醚环化糊精。
6.根据权利要求5的制剂，其中磺烷基醚环化糊精是磺丁基醚β-环化糊精。
7.根据前述任何一项权利要求的制剂，用于静脉内使用。
8.根据前述任何一项权利要求的制剂，其中磷雌氮芥是用于静脉内给药的可药用盐形式。
9.根据权利要求8的制剂，其中磷雌氮芥是N-甲基葡萄糖胺盐的形式。
10.根据前述任何一项权利要求的制剂，用于治疗癌症。
11.在权利要求10中要求保护的制剂，其中癌症是前列腺癌，乳腺癌，黑素瘤，肺癌，胰腺癌，结肠直肠癌，卵巢癌或脑癌。
12.根据权利要求1的制剂，其中肠胃外可接受的载体是肠胃外用生理溶液，其含有磺烷基醚环化糊精，且磷雌氮芥采用冻干形式。
13.根据权利要求1的制剂，其中磷雌氮芥和磺烷基醚环化糊精相混合。
14.一种产品，其含有
(i)包含肠胃外可接受的载体或稀释剂，磷雌氮芥和磺烷基醚环化糊精的药物制剂，以及
(ii)一种或多种化学治疗剂；作为抗癌治疗中同时、分开或相继使用的联合制品。
15.根据权利要求14的产品，其中磺烷基醚环化糊精是磺丁基醚β-环化糊精。
16.根据权利要求14或15的产品，其中化学治疗剂可以任选地包裹在脂质体中，这些治疗剂选自紫杉烷，紫杉烷衍生物，CPT-11，喜树碱及其衍生物，多柔比星，伊达比星或表柔比星，依托泊苷，诺威本，长春碱，卡铂，顺铂，Sugen SU 6668和Sugen SU 5416。
17.根据权利要求14的用于静脉内使用的产品。
18.根据权利要求14的产品，用于治疗前列腺癌，乳腺癌，黑素瘤，肺癌，胰腺癌，结肠直肠癌，卵巢癌或脑癌。
19.权利要求7中定义的制剂，用于抑制或减少与静脉内施用磷雌氮芥和其可药用盐相关的副作用。
20.根据权利要求19的制剂，其中副作用包含注射部位的溃疡性损伤和血栓性静脉炎。
21.一种产品，包含冻干形式的磷雌氮芥和含有磺烷基醚环化糊精的肠胃外用生理溶液。
22.磷雌氮芥和磺烷基醚环化糊精在生产用于肠胃外给药的药物中的用途。
23.根据权利要求22的用途，其中药物用于静脉内给药。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9921958.6A GB9921958D0 (en) | 1999-09-16 | 1999-09-16 | Formulations for parenteral use of estramustine phosphate and sulfoalkylether-cyclodextrins |
| GB9921958.6 | 1999-09-16 |
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| Publication Number | Publication Date |
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| CN1374857A true CN1374857A (zh) | 2002-10-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00812947A Pending CN1374857A (zh) | 1999-09-16 | 2000-08-03 | 肠胃外用磷雌氮芥和磺烷基醚环化糊精制剂 |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US6730664B1 (zh) |
| EP (1) | EP1212041A1 (zh) |
| JP (1) | JP2003509356A (zh) |
| KR (1) | KR20020059401A (zh) |
| CN (1) | CN1374857A (zh) |
| AU (1) | AU777684B2 (zh) |
| BR (1) | BR0014062A (zh) |
| CA (1) | CA2385065A1 (zh) |
| CZ (1) | CZ2002944A3 (zh) |
| EA (1) | EA003936B1 (zh) |
| GB (1) | GB9921958D0 (zh) |
| HU (1) | HUP0300185A3 (zh) |
| IL (1) | IL148408A0 (zh) |
| MX (1) | MXPA02002855A (zh) |
| NO (1) | NO20021270L (zh) |
| PL (1) | PL356026A1 (zh) |
| SK (1) | SK3462002A3 (zh) |
| WO (1) | WO2001019339A1 (zh) |
| ZA (1) | ZA200201744B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6869939B2 (en) * | 2002-05-04 | 2005-03-22 | Cydex, Inc. | Formulations containing amiodarone and sulfoalkyl ether cyclodextrin |
| NZ592293A (en) * | 2005-11-28 | 2012-10-26 | Verrow Pharmaceuticals Inc | Compositions comprising an oligosaccharide such as a cyclodextrin for reducing the nephrotoxicity of other drugs |
| US7658913B2 (en) * | 2005-11-28 | 2010-02-09 | Verrow Pharmaceuticals, Inc. | Compositions useful for reducing nephrotoxicity and methods of use thereof |
| US20110207764A1 (en) * | 2010-02-23 | 2011-08-25 | Valery Alakhov | Cyclopolysaccharide compositions |
| US8383663B2 (en) | 2010-07-19 | 2013-02-26 | Supratek Pharma Inc. | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
| WO2024074600A1 (en) * | 2022-10-05 | 2024-04-11 | Institut Gustave Roussy | An oral liquid composition of vinorelbine |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1523035A (en) * | 1976-03-10 | 1978-08-31 | Leo Ab | Derivatives of estradiol - 17 - dihydrogen phosphates |
| JPS59108800A (ja) | 1982-12-13 | 1984-06-23 | Japan Atom Energy Res Inst | 誘導ミサイル作用および制癌剤の徐放性機能をもつ微粒子 |
| CA1260393A (en) * | 1984-10-16 | 1989-09-26 | Lajos Tarcsay | Liposomes of synthetic lipids |
| KR0166088B1 (ko) | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
| US5602112A (en) * | 1992-06-19 | 1997-02-11 | Supergen, Inc. | Pharmaceutical formulation |
| GB9419153D0 (en) * | 1994-09-22 | 1994-11-09 | Erba Carlo Spa | Estramustine formulations with improved pharmaceutical properties |
| US5744460A (en) * | 1996-03-07 | 1998-04-28 | Novartis Corporation | Combination for treatment of proliferative diseases |
| US20020039594A1 (en) | 1997-05-13 | 2002-04-04 | Evan C. Unger | Solid porous matrices and methods of making and using the same |
-
1999
- 1999-09-16 GB GBGB9921958.6A patent/GB9921958D0/en not_active Ceased
-
2000
- 2000-08-03 IL IL14840800A patent/IL148408A0/xx unknown
- 2000-08-03 KR KR1020027003383A patent/KR20020059401A/ko not_active Application Discontinuation
- 2000-08-03 US US10/070,416 patent/US6730664B1/en not_active Expired - Fee Related
- 2000-08-03 CA CA002385065A patent/CA2385065A1/en not_active Abandoned
- 2000-08-03 PL PL00356026A patent/PL356026A1/xx unknown
- 2000-08-03 AU AU69939/00A patent/AU777684B2/en not_active Ceased
- 2000-08-03 HU HU0300185A patent/HUP0300185A3/hu unknown
- 2000-08-03 BR BR0014062-7A patent/BR0014062A/pt not_active IP Right Cessation
- 2000-08-03 WO PCT/EP2000/007680 patent/WO2001019339A1/en not_active Application Discontinuation
- 2000-08-03 JP JP2001522974A patent/JP2003509356A/ja not_active Withdrawn
- 2000-08-03 SK SK346-2002A patent/SK3462002A3/sk unknown
- 2000-08-03 CZ CZ2002944A patent/CZ2002944A3/cs unknown
- 2000-08-03 EA EA200200370A patent/EA003936B1/ru not_active IP Right Cessation
- 2000-08-03 MX MXPA02002855A patent/MXPA02002855A/es unknown
- 2000-08-03 CN CN00812947A patent/CN1374857A/zh active Pending
- 2000-08-03 EP EP00958398A patent/EP1212041A1/en not_active Withdrawn
-
2002
- 2002-03-01 ZA ZA200201744A patent/ZA200201744B/en unknown
- 2002-03-14 NO NO20021270A patent/NO20021270L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| SK3462002A3 (en) | 2002-08-06 |
| CA2385065A1 (en) | 2001-03-22 |
| EA200200370A1 (ru) | 2002-10-31 |
| MXPA02002855A (es) | 2003-07-21 |
| NO20021270D0 (no) | 2002-03-14 |
| ZA200201744B (en) | 2004-01-28 |
| GB9921958D0 (en) | 1999-11-17 |
| EP1212041A1 (en) | 2002-06-12 |
| WO2001019339A1 (en) | 2001-03-22 |
| HUP0300185A3 (en) | 2007-02-28 |
| BR0014062A (pt) | 2002-12-31 |
| US6730664B1 (en) | 2004-05-04 |
| CZ2002944A3 (cs) | 2002-08-14 |
| PL356026A1 (en) | 2004-05-31 |
| HUP0300185A2 (en) | 2003-05-28 |
| IL148408A0 (en) | 2002-09-12 |
| AU6993900A (en) | 2001-04-17 |
| AU777684B2 (en) | 2004-10-28 |
| EA003936B1 (ru) | 2003-10-30 |
| NO20021270L (no) | 2002-03-14 |
| JP2003509356A (ja) | 2003-03-11 |
| KR20020059401A (ko) | 2002-07-12 |
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