CN1053550A - 鬼臼乙叉甙-2-二甲基氨基化合物的冷冻干燥制剂 - Google Patents
鬼臼乙叉甙-2-二甲基氨基化合物的冷冻干燥制剂 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A—HUMAN NECESSITIES
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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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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Abstract
本发明涉及冷冻干燥制剂,其包括(1)约5-约
50W/W%非挥发酸和/或其盐,(2)约10-约
95W/W%4-O-(2-脱氧-2-二甲氨基-4,6-O-亚
乙基-β-D-吡喃葡萄糖基)-4′-脱甲基-4-表鬼臼
脂素盐酸盐和(3)0-约85W/W%作为稳定剂的至
少一种糖。
Description
本发明涉及鬼臼乙叉甙衍生物的稳定冷冻干燥制剂,其用做抗肿瘤剂。
4-0-(2-脱氧-2-二甲基氨基-4,6-0-亚乙基-β-D-吡喃葡萄糖基)-4′-脱甲基-4-表鬼臼脂素盐酸盐(今后缩写为鬼臼乙叉甙-2-二甲基氨基化合物)是抗肿瘤剂鬼臼乙叉甙的衍生物。鬼臼乙叉甙-2-二甲基氨基化合物具有优良的溶解度并且显示出抗肿瘤活性(cf.usp4,716,221),而鬼臼乙叉甙的溶解度不好。
但鬼臼乙叉甙-2-二甲基氨基化合物在水溶液中不稳定,这使其不易长期贮存。
通过仅将鬼臼乙叉甙-2-二甲基氨基化合物溶在蒸馏水中,然后冷冻干燥得到的药物制剂存在着这样的缺陷:当该化合物重新与水配制时,其溶液的PH将增加,从而造成结晶析出。
为改善重新配制对制剂组成进行了各种研究,结果本发明者已发现含非挥发酸和/或其盐的鬼臼乙叉甙-2-二甲基氨基化合物的冷冻干燥制剂具有良好重新配制性能从而无结晶析出发生,其在贮存时还显示出良好的稳定性并且几乎不形成分解产物,且它的稳定性通过加入糖进一步提高。由此本发明已完成。
本发明涉及鬼臼乙叉甙-2-二甲基氨基化合物的冷冻干燥制剂。本发明提供的冷冻干燥制剂包括:(1)约5-约50W/W%的非挥发酸和/或其盐,(2)约10-约95W/W%4-0-(2-脱氧-2-二甲基氨基-4,6-0-亚乙基-β-D-吡喃葡萄糖基)-4′-脱甲基-4-表鬼臼脂素盐酸盐和(3)0-约85W/W%作为稳定剂的至少一种糖。
本发明中所用的鬼臼乙叉甙-2-二甲基氨基化合物通常以其盐酸盐形式使用,见日本专利申请KOKAI No.61-227590。该盐酸盐具有三种多晶型结晶形式,一种为无水结晶(今后简称为α结晶),另二种为二水合物结晶(今后简称为β结晶和ν结晶)。本发明的任何一种结晶形式都是可用的。
作为本发明中可用的非挥发酸或其盐,只要它们在室温下是液体或固体,在PH3至5范围内(该范围内鬼臼乙叉甙-2-二甲基氨基化合物是相对稳定的并具有好的溶解度)具有所需的缓冲作用,所用的酸或其盐就不受任何具体的抑制,它们是药用的及药理可接受的。这些酸包括无机酸如磷酸,硫酸等:含6个碳原子的含羟羧酸如柠檬酸,葡萄糖酸等;含4个碳原子的二羧酸如琥珀酸,酒石酸,富马酸,马来酸等;含2个碳原子的羧酸,如氨基乙酸等。这些酸中,尤其优选磷酸。这些酸的盐有碱金属或碱土金属盐如钠盐,钾盐,镁盐等,但一般优选碱金属盐。这些酸或其盐可两个和/或多个合起来用。加到制剂中的这些酸和/或其盐的量依赖于这些酸和/或其盐的缓冲效果,但范围一般是以1份重鬼臼乙叉甙-2-二甲基氨基化合物计,由约0.1至5份重,优选约0.1-4份重,更优选0.2-3份重。本发明制剂的PH不低于3,不高于5,作为重新配制溶液的PH,优选不低于3.0,不高于4.5。
如必须需要的话,本发明制剂还可含有糖等。糖的例子包括含5-6个碳原子的糖醇如甘露糖醇,山梨糖醇,木糖醇,肌醇等;二糖如乳糖,麦芽糖,蔗糖等。在这些糖中,虽不存在特殊限制,但优选乳糖,用这些糖改善了贮存期间鬼臼乙叉甙-2-二甲基氨基化合物的稳定性。糖的量以1份重鬼臼乙叉甙-2-二甲基氨基化合物计,为0-30份重,优选约0.1-10份重。从把该化合物制成其药物制剂看,优选糖量为约0.1-约4份重。
在本发明冷冻干燥制剂中,鬼臼乙叉甙-2-二甲基氨基化合物占组合物总重量约10-约95%(W/W:除非另有说明,今后皆为W/W),优选约15-约80%,更优选约30-约50%,非挥发酸和/或其盐占组合物总重的约5-约50%,优选约15-约35%,更优选约20-约30%;糖占组合物总重的约0-约85%,优选约0-约70%,更优选约30-约50%。
本发明冷冻干燥制剂如下制备,将鬼臼乙叉甙-2-二甲基氨基化合物和非挥发酸和/或其盐及如必要的话,再加上糖一起溶于水用于制备注射剂,如必要,用氢氧化钠等将PH调到约3-约5,优选约3.0-约4.5,得到水溶液。当使用非挥发酸的盐时,鬼臼乙叉甙-2-二甲基氨基化合物可能由于其PH不能溶解,在这种情况下,使用非挥发酸,将PH降低到3以下由此来溶解鬼臼乙叉甙-2-二甲基氨基化合物。例如,优选的水溶液组合物包括约5-约15mg/ml鬼臼乙叉甙-2-二甲基氨基化合物,约1-约10mg/ml非挥发酸和/或其盐和0-约50mg/ml糖。
由此得到的水溶液于-5--60℃下冷冻,然后在真空度为0.01-200Pa减压下使水升华,从而得到本发明的冷冻干燥制剂。
因此得到的冷冻干燥制剂通常通过加溶解液如水重新溶解以制备注射剂,所得到的溶液用作注射液。在这种情况下,溶解液的PH值优选约3-约5范围。
下面由实施例和试验例说明本发明,但这不代表任何限制。
实施例1
将α结晶溶于50mM磷酸盐缓冲液中以使浓度为10mg/ml,该缓冲液是通过将50mM磷酸水溶液和50mM磷酸二氢钠水溶液混合得到的,其PH为3.0。然后用1N氢氧化钠溶液调节所得溶液PH至3.0。将该溶液按1ml/小瓶的比例分到小瓶中,冷冻干燥,得到本发明的组合物1(含约63%鬼臼乙叉甙-2-二甲基氨基化合物和约37%磷酸和其盐)。
实施例2
将α结晶和甘露糖醇溶于50mM磷酸盐缓冲液中,从而使它们的浓度分别达到10mg/ml和40mg/ml,该缓冲液PH如实施例1所示为3.0。然后用1N氢氧化钠溶液调节所得溶液PH至3.0。按实施例1同样方式冷冻干燥该溶液得本发明的组合物2(含约18%鬼臼乙叉甙-2-二甲基氨基化合物,约11%磷酸和其钠盐,约71%甘露糖醇)。
实施例3
将α结晶和肌醇溶于50mM磷酸盐缓冲液以使它们的浓度分别达到10mg/ml和40mg/ml,该缓冲液PH如实施例1所示为3.0。然后用1N氢氧化钠溶液调节所得溶液的PH至3.0。按实施例1中的同样方法冷冻干燥该溶液,得到本发明的组合物3(含约18%鬼臼乙叉甙-2-二甲基氨基化合物,约11%磷酸和其钠盐,约71%肌醇)。
实施例4
将α结晶和乳糖溶于50mM磷酸盐缓冲液中以使它们的浓度分别达到10mg/ml和40mg/ml,所用缓冲液的PH如实施例1中所示为3.0。然后用1N氢氧化钠水溶液调节所得溶液PH至3.0。按实施例1中同样方法冷冻干燥该溶液,得本发明的组合物4(含约18%鬼臼乙叉甙-2-二甲基氨基化合物,约11%磷酸和其钠盐,约71%乳糖)。
实施例5
将α结晶和麦芽糖溶于50mM磷酸盐缓冲液以使它们的浓度分别达到10mg/ml和40mg/ml,该缓冲液PH如实施例1所示为3.0。然后用1N氢氧化钠溶液调节所得溶液PH至3.0。按实施例1同样方法冷冻干燥该溶液,得到本发明的组合物5(含约18%鬼臼乙叉甙-2-二甲基氨基化合物,约11%磷酸和其钠盐,约71%麦芽糖)。
实施例6
将α结晶和蔗糖溶于50mM磷酸盐缓冲液中以使包括的浓度分别达到10mg/ml和40mg/ml,所用缓冲液的PH如实施例1所示为3.0。然后用1N氢氧化钠溶液调节所得溶液PH至3.0。按实施例1中同样方法冷冻干燥该溶液,得到本发明的组合物6(含约18%鬼臼乙叉甙-2-二甲基氨基化合物,约11%磷酸和其钠盐。71%蔗糖)。
实施例7
将α结晶溶于50mM柠檬酸盐缓冲液以使其浓度达到10mg/ml,该缓冲液是通过混合50mM柠檬酸水溶液和50mM柠檬酸三钠水溶液得到的,其PH为3.0。然后用50mM柠檬酸三钠水溶液调节所得溶液的PH至3.0。按实施例1同样方法冷冻干燥该溶液,得到本发明的组合物7(含约49%鬼臼乙叉甙-2-二甲基氨基化合物和约51%柠檬酸和其钠盐)。
实施例8
将α结晶和甘露糖醇溶于50mM柠檬酸盐缓冲液中以使它们的浓度分别达到10mg/ml和40mg/ml,所用缓冲液PH如实施例7所示为3.0。然后用50mM柠檬酸三钠水溶液调节所得溶液PH至3.0。按实施例1同样方法冷冻干燥该溶液,得到本发明的组合物8(含约17%鬼臼乙叉甙-2-二甲基氨基化合物,约17%柠檬酸和其钠盐,约66%甘露糖醇)。
实施例9
将β结晶溶于50mM磷酸盐缓冲液中以使其浓度达到10mg/ml,该缓冲液PH为3.0。然后用1N氢氧化钠溶液调节所得溶液的PH至3.0。按2ml/小瓶比例将该溶液分到小瓶中,然后冷冻干燥,得到本发明的组合物9(含约63%鬼臼乙叉甙-2-二甲基氨基化合物和约37%磷酸和其钠盐)。
实施例10
将β结晶溶于50mM磷酸盐缓冲液中以使其浓度达到10mg/ml,所用缓冲液PH与实施例1中相同。然后用1N氢氧化钠溶液调节所得溶液PH至4.0。按实施例9同样方法冷冻干燥该溶液,得到本发明的组合物10(含约63%鬼臼乙叉甙-2-二甲基氨基化合物和约37%磷酸和其钠盐)。
实施例11
按实施例9所述,将β结晶溶于25mM磷酸盐以使其浓度达到10mg/ml,该缓冲液是通过混合25mM磷酸水溶液和25mM磷酸二氢钠水溶液得到的,其PH为3.0。然后用1N氢氧化钠溶液调节所得溶液PH至3.5。按实施例9同样方法冷冻干燥该溶液,得本发明的组合物11(含约77%鬼臼乙叉甙-2-二甲氨基化合物和约23%磷酸和其钠盐)。
实施例12
将β结晶和甘露糖醇溶于如实施例9中所述50mM磷酸盐缓冲液中以使它们的浓度分别达到10mg/ml和4mg/ml。然后用1N氢氧化钠溶液调节所得溶液PH至3.5。按实施例9同样方法冷冻干燥该溶液,得本发明的组合物12(含约50%鬼臼乙叉甙-2-二甲氨基化合物,约30%磷酸和其钠盐,约20%甘露糖醇)。
实施例13
将β结晶和乳糖溶于如实施例9中所述的50mM磷酸盐缓冲液中以使它们的浓度达到10mg/ml。然后用1N氢氧化钠溶液调节所得溶液PH至3.0。按实施例9中同样方法冷冻干燥该溶液,得到本发明的组合物13(含约37%鬼臼乙叉甙-2-二甲基氨基化合物,约26%磷酸和其钠盐,及约37%乳糖)。
实施例14
按实施例9所述,将β结晶和山梨糖醇溶于25mM磷酸盐缓冲液以使它们的浓度达到10mg/ml。然后用1N氢氧化钠溶液调节所得溶液PH至3.5。按实施例9中同样方法冷冻干燥该溶液,得本发明的组合物14(含约42%鬼臼乙叉甙-2-二甲氨基化合物,约17%磷酸和其钠盐及约41%山梨糖醇)。
实施例15
如实施例9所述,将β结晶和木糖醇溶于25mM磷酸盐缓冲液中以使它们的浓度达到10mg/ml。然后用1N氢氧化钠溶液调节所得溶液的PH至3.5。按实施例9中同样方法冷冻干燥该溶液,得本发明的组合物15(含约42%鬼臼乙叉甙-2-二甲基氨基化合物,约17%磷酸和其钠盐,及约41%木糖醇)。
比较实施例1
将α结晶溶于水中以使其浓度达到10mg/ml,然后用1N盐酸调节所得溶液PH至3.0。按实施例1中同样方法冷冻干燥该溶液,得比较组合物1。
比较实施例2
将α结晶和乳糖溶于水中以使它们的浓度达到10mg/ml。然后按实施例1中同样方法冷冻干燥所得溶液,得比较组合物2(含约50%鬼臼乙叉甙-2-二甲氨基化合物和约50%乳糖)。
下面进行的试验实施例是用来说明含鬼臼乙叉甙-2-二甲氨基化合物的本发明冷冻干燥制剂在贮存时有优异的稳定性并且其重配性也得到了改善。
试验实施例
本发明组合物1-15,比较组合物1(其PH用挥发酸调节,随后冷冻干燥)和比较组合物(其是通过单独加入糖,不调节PH,然后冷冻干燥得到的)在冷冻干燥及60-65℃贮存一星期后马上检验它们的外观,重配性,PH和鬼臼乙叉甙-2-二甲基氨基化合物的剩余量。剩余量是通过液相色谱测定的,其中鬼臼乙叉甙-2-二甲氨基化合物和分解产物的总量应为100。加1ml蒸馏水到实施例1-8和比较实施例1-2的每一小瓶中,加2ml蒸馏水到实施例9-15的每一小瓶中,从而使鬼臼乙叉甙-2-二甲氨基化合物的浓度为10mg/ml,然后用溶解干燥粉末的程度和溶解后结晶有无析出来观察重配性。结果当比较实施例1和2组合物重配时,它们在PH为5或更高下析出了结晶,因此,比较组合物都不适宜用于制备注射剂。
而本发明组合物1-15显示出如表中所示的好的再溶性,无结晶析出,PH改变很小。结果表明它们具有好的贮存稳定性。通过加糖,剩余量进一步提高。
表
样品 | 外观 | 重配性 | PH | 剩余量(%) |
实施例1实施例2实施例3实施例4实施例5实施例6实施例7实施例8实施例9实施例10实施例11实施例12实施例13实施例14实施例15比较实施例1比较实施例2 | 好好好好好好好好好好好好好好好好好 | 好好好好好好好好好好好好好好好有结晶有结晶 | 3.33.33.33.33.33.33.23.23.24.44.13.73.03.63.7>5.0>5.0 | 89.893.899.199.399.198.488.593.290.498.999.099.199.498.298.4-- |
如上所述,本发明提供了具有良好重配性和稳定PH和剩余量的鬼臼乙叉甙-2-二甲氨基化合物的制剂。
Claims (11)
1、制备冷冻干燥制剂的方法,该方法包括:将(1)非挥发酸和/或其盐,(2)4-0-(2-脱氧-2-二甲氨基-4,6-0-亚乙基-β-D-吡喃葡萄糖基)-4′-脱甲基-4-表鬼臼脂素盐酸盐和(3)作为稳定剂的至少一种糖溶于水用于注射,得到溶液,然后减压冷冻干燥该溶液,每种成份在冷冻干燥制剂中的含量分别为:(1)约5-约50W/W%,(2)约10-约95W/W%和(3)0-约85W/W%。
2、根据权利要求1制备冷冻干燥制剂的方法,其中冷冻干燥是在-5--60℃温度下进行的。
3、根据权利要求1制备冷冻干燥制剂的方法,其中减压是在真空度0.01-200Pa下进行的。
4、根据权利要求1制备冷冻干燥制剂的方法,其中当所得冷冻干燥制剂再溶于蒸馏水时,所得溶液的PH值不小于3但小于5。
5、根据权利要求1制备冷冻干燥制剂的方法,其中所说非挥发酸和/或其盐选自磷酸和其盐的混合物,选自含6个碳原子的含羟羧酸,含4个碳原子的二羧酸和氨基乙酸的一种酸和/或它的盐。
6、根据权利要求1制备冷冻干燥制剂的方法,其中所说非挥发酸和其盐是磷酸和其碱金属盐或柠檬酸和其碱金属盐。
7、根据权利要求1制备冷冻干燥制剂的方法,其中所说糖是含5-6个碳原子的糖醇或二糖。
8、根据权利要求1制备冷冻干燥制剂的方法,其中所说糖选自乳糖、麦芽糖、蔗糖和甘露糖醇。
9、根据权利要求1制备冷冻干燥制剂的方法,其中该制剂包括(1)约15-约35W/W%磷酸和其碱金属盐,(2)约15-约80W/W%4-0-(2-脱氧-2-二甲氨基-4,6-0-亚乙基-β-D-吡喃葡萄糖基)-4′-脱甲基-4-表鬼臼脂素盐酸盐和(3)0-约70W/W%乳糖。
10、根据权利要求1制备冷冻干燥制剂的方法,其中该制剂包括:(1)约20-约30W/W%磷酸和其碱金属盐,(2)约30-约50W/W%4-0-(2-脱氧-2-二甲氨基-4,6-0-亚乙基-β-D-吡喃葡萄糖基)-4′-脱甲基-4-表鬼臼脂素盐酸盐和(3)约30-约50W/W%乳糖。
11、根据权利要求10制备冷冻干燥制剂的方法,其中当该制剂再溶于水用于注射时,该制剂的PH值不小于3但小于5。
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AU1678900A (en) * | 1998-08-11 | 2000-03-06 | All India Institute Of Medical Sciences | A novel liposomal formulation useful in treatment of cancer and other proliferation diseases |
WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
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EP0438091B1 (en) | 1993-09-08 |
US5326753A (en) | 1994-07-05 |
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ES2060208T3 (es) | 1994-11-16 |
DE69100334T2 (de) | 1994-03-10 |
AU632654B2 (en) | 1993-01-07 |
HU205857B (en) | 1992-07-28 |
EP0438091A2 (en) | 1991-07-24 |
HU910166D0 (en) | 1991-08-28 |
AU6945191A (en) | 1991-07-25 |
HUT56499A (en) | 1991-09-30 |
DE69100334D1 (de) | 1993-10-14 |
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