CN1148805A - 稳定度卡霉素衍生物的方法 - Google Patents
稳定度卡霉素衍生物的方法 Download PDFInfo
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Classifications
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
以式(I)为代表的稳定的度卡霉素衍生物:其中R是低级烷基、烯丙基或苄基,X是氯原子或是溴原子,通过将至少一种选自糖、电解质、水溶性聚合物、多羟基醇及表面活性剂中的化合物加入到含有度卡霉素衍生物的溶液中来制备。也提供了含有稳定的度卡霉素衍生物的冷冻干燥了的药物制剂。
Description
技术领域
本发明涉及一种使度卡霉素衍生物稳定的方法及含有这种稳定的衍生物的制剂。
背景技术
但是,度卡霉素衍生物,包括呈氢溴化物形式的化合物A,在水溶液中非常易分解。因此,在需要长期贮存的药物中,这些化合物的不稳定性就是一个主要问题。所以,就需要能长期保存的,含有度卡霉素衍生物的稳定的药物制剂。
本发明公开
其中R代表低级烷基、烯丙基、或者是苄基,X代表氢原子或溴原子,本方法的特征在于:在含有所述的度卡霉素衍生物的溶液中存在至少一种选自糖、电解质、水溶性聚合物、多羟基醇及表面活性剂成分。使之稳定的优选方法是,将含有度卡霉素衍生物(其结构式如(I)式所示)及糖溶液冷冻、干燥。更加优选的方法是,将另外含有选自电解质、水溶性聚合物、多羟基醇和表面活性剂中至少一种成份的溶液冷冻干燥。本发明提供了含有度卡霉素衍生物的冷冻干燥的药物制剂,此制剂经过上述方法而被稳定。
就式(I)而言,低级烷基意指含有1-6个碳原子的直链或支链烷基,例如,甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、及己基。
如式(I)所代表的度卡霉素衍生物可以通过美国专利号5,070,092所描述的方法来制备。
表1
化合物序号 | X | IR(KBr),V(cm-1) |
1(化合物A) | Br | 3475,3232,2944,1698,1491,1410,1313,1217,1110 |
1(化合物)* | Br | 1717,1692,1608,1525,1490,1409,1310,1218,1167,1108 |
2 | Cl | 2940,1698,1637,1491,1410,1314,1218,1154,1109 |
*氢溴化物单水合物
根据本发明,式(I)为代表的度卡霉素衍生物及至少一种选自糖、电解质、水溶性聚合物、多羟基醇、表面活性剂的成分溶于溶中,优选酸性溶性,最优选的溶液是PH5或更低。将所得溶液在无菌条件下用滤膜过滤,然后冷冻、干燥。
就糖而言,可以用乳糖、蔗糖、棉子糖、葡聚糖等。优选乳糖。溶液中糖的浓度是0.005至1000mg/ml,优选1至500mg/ml。对电解质,任何药学上可接受而又能增加溶液的离子强度的电解质都可采用。例如,无机酸诸如盐酸、氢溴酸、氢碘酸、硫酸、碳酸、硅酸、磷酸、硼酸;有机酸,如柠檬酸、醋酸;以及它们的钠盐、钾盐等等都可采用。溶液中电解质的浓度是0.001到500mg/ml,优选范围是0.01到100mg/ml。对水溶性聚合物而言,可采用聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、羟基乙烯聚合物等等,其浓度为1至1000mg/ml,优选10至500mg/ml。对于多羟基醇可采用甘油、丙二醇,其浓度为10到1000mg/ml,优选100至500mg/ml。对于表面活性剂可采用聚氧乙烯脱水山梨醇脂肪酸酯(吐温)、氢化聚氧乙烯蓖麻油等等,其浓度为0.01至5000mg/ml,优选0.1到500mg/ml。被冷冻、干燥的溶液中度卡霉素衍生物的浓度是0.001至1000mg/ml,优选0.1至10mg/ml。溶液的冷冻、干燥是在适应的条件下进行的。例如,先将溶液于-50℃冷冻5小时(预冷冻),在-30℃、0.05mbar下干燥30小时,然后于0℃,0.05mbar干燥15小时(初干燥)。再将其置于25℃、0.05mbar干燥15小时(第二次干燥)。
在具有代表性例子中,此溶液在一个小瓶中冷冻干燥,然后,将含有冷冻、干燥了的试剂的小瓶用橡皮塞子封住,再用铝盖封,籍此,就得到了含有度卡霉素衍生物的、冷冻、干燥的药物制剂。
当度卡霉素的冷冻、干燥制剂用应于临床时,把这个冷冻干燥了的药物制剂溶于含有稳定剂的溶液中,此稳定剂选自电解质、水溶性聚合物、多羟基醇及表面活性剂中的至少一种。
本发明中的药物制剂还可以含有适宜的、药学上可接受的物质,如,抗氧剂、防腐剂、缓冲液、镇痛剂、增溶剂、等渗剂、保存剂、稳定剂、赋形剂、粘合剂、崩解剂、湿润剂、润滑剂、着色剂、芳香剂、矫味剂、包衣、悬浮剂、乳化剂、成形剂、表面活性剂等等。例如,配制的制剂中还可含有抗氧剂,如抗坏血酸、维生素E、丁羟基甲苯和苄羧基甲苯;防腐剂如:对羟基苯甲酸酯类、氯代丁醇;缓冲液,如;磷酸和柠檬酸;镇痛剂,如:苯甲醇和利多卡因;赋形剂,如:结晶纤维素、羟丙基淀粉、淀粉、及玉米淀粉;粘合剂如:支链淀粉、聚乙烯醇和羟丙基纤维素,崩解剂,如:羧甲基纤维素及Croscarmellose sodium;润滑剂如:硬脂酸镁、滑石、氢化的油等等。
本发明所述的药物制剂不仅可以制成注射剂,还可以是口服给药形式如片剂、胶囊剂及颗粒剂,还可以是栓剂形式的直肠给药。
本发明中的药物制剂用作抗肿瘤药时,它的剂量及给药方案将随着各种因素的变化而变化,比如,病人的年龄、体重、及身体状况等。例如,当这个制剂用作抗肿瘤注射剂时,有效成分的适宜剂量是0.0001至10mg/kg。可以每日给药一次(单次或连续给药)或者是间歇的每周一至三次,也可以是每三周一次。
以下有代表性的实施例及实施例更详细、具体地阐述了本发明。
实施本发明的最佳方式:
实施例1
在本实施例中,将50mg的柠檬酸、100mg的化合物A氢溴化物及5000mg的乳糖溶解于蒸馏水中,总体积为200ml。将所得溶液放入15-ml的玻璃瓶中,每份2ml,然后,减压下冷冻、干燥。冷冻干燥后,在氮气流中将压力回复到常压,每个小瓶用橡皮塞及铝盖封住,这样就得到了含有化合物A的冷冻干燥制剂。
实施例2
在本实施例中,将50mg的柠檬酸、100mg的化合物A氢溴化物,5000mg的乳糖及100mg的溴化钠溶于蒸馏水中,总体积为200ml。将所得溶液放入15-ml的玻璃瓶中,每份2ml,减压下冷冻、干燥。然后,在氮气流中将压力回复到常压,每个小瓶用橡皮塞及铝盖封住,从而得到含有化合物A的冷冻干燥制剂。
实施例3
在本实施例中,将50mg的柠檬酸、100mg的化合物A氢溴化物,5000mg的乳糖、100mg的溴化钠及500mg的聚氧乙烯脱水山梨醇单油酸酯(吐温80)溶于蒸馏水中,总体积为200ml。将所得溶液放入15-ml的玻璃瓶中,每份2ml,减压下冷冻干燥。冻干后,使压力在氮气流中恢复至常压,把每个小瓶用橡皮塞和铝盖封住,就得到了含有化合物A的冷冻干燥制剂。
实施例4
在本实施例中,将50mg的柠檬酸及100mg的化合物A氢溴化物溶于蒸馏水中,总体积为200ml。将所得溶液置于15-ml的小玻璃瓶中,每份2ml,减压下冷冻干燥。冻干后,将压力在氮气流中回复至常压,每个小瓶用橡皮塞及铝盖封住,就得到了含有化合物A的冷冻干燥制剂。
试验例1
将化合物A氢溴化物(1mg)溶于蒸馏水中,加水至10ml(对照溶液)。另外,将0.5mg的柠檬酸及1mg的化合物A氢溴化物溶于蒸馏水中,其中含有1mg的溴化钠(试验溶液1),或者含有1mg的溴化钠及5mg的吐温-80(试验溶液2),加水至10ml。所有试验溶液的PH值均调至3.6。将对照溶液和试验溶液分别放15ml的小玻璃瓶中,于25℃恒温保存。每一溶液取1ml按预定的时间间隔测定。每个试验样品溶液中的保留下来的化合物A的含量用高效液相色谱法分析,其结果如表2所示。高效液相色谱条件
柱子: Inertsil ODS-2,6.0φ×250mm
流动相: 0.05M磷酸盐缓冲液(PH5.9)/乙腈(48/52体积比)
流速: 1.0ml/min
检测波长:330nm
表2
水溶液中化合物A的稳定性(25℃)
试验溶液 | 化合物A的含量(%) | ||
0小时(开始) | 2小时 | 4小时 | |
对照溶液试验溶液1试验溶液2 | 100.0100.0100.0 | 95.595.798.6 | 91.993.297.9 |
从表2中对照溶液的结果可以看出,化合物A在水溶液中随着时间延长而分解。也证实了向此溶液中单独加入溴化钠(试验溶液1)或者是加入溴化钠和吐温-80(试验溶液2)可以提高化合物A的稳定性。从这些结果看,很明显,溴化钠的加入或者是溴化钠和吐温-80的加入,提高了冻干制剂制备过程中水溶液中的化合物A的稳定性,及冻干制剂给病人服药时重新配制过程中化合物A的稳定性。因此,带给病人的化合物A的分解产物的可能性减少。
实验例2
将5mg柠檬酸及1mg化合物A氢溴化物溶于含有1g丙二醇(试验溶液3)或者1g聚乙二醇400(试验溶液4)蒸馏水中,加水至10ml。将两种溶液的PH均调至3.0。把试验溶液分别放于15ml玻璃瓶中,于40℃恒温储存。每一溶液按预定的时间间隔取1ml样品测定。每一试验样品溶液中残余的化合物A的含量用高效液相色谱分析,其结果见表3。高效液相色谱条件
柱子: Inertsil ODS-2,6.0φ×250mm
流动相: 0.05M磷酸盐缓冲液(PH5.9)/乙腈(48/52体积比)
流速: 1.0ml/min
检测波长:330nm
表3
水溶液中化合物A的稳定性(40C)
试验溶液 | 化合物A的含量(%) | ||
0小时(开始) | 3小时 | 6小时 | |
试验溶液3试验溶液4 | 100.0100.0 | 68.484.9 | 46.870.8 |
试验例3
将实施例1至4中所制得的冻干制剂于60℃恒温储存30天。每一制剂中所剩存的化合物A的含量用高效液相色谱法分析,其结果如表4所示。
表4
化合物贮藏稳定性(在60℃下,30天)
实施例序号 化合物A的含量(%) |
实施例1 100.0实施例2 100.4实施例3 99.3实施例4 97.6 |
从表4的结果可以看出,很显然,含有化合物A的冻干制剂中加入糖以后其稳定性提高了。
工业上的应用
本发明提供了度卡霉素衍生物稳定化的方法及含有它的制剂。
Claims (6)
1.一种稳定通式(I)的度卡霉素衍生物的方法,
其中R代表低级烷基、烯丙基或者是苄基,X代表氯原子或是溴原子,其特点是,从糖、电解质、水溶性聚合物、多羟基醇及表面活性剂中至少选出一种化合物加入到含有度卡霉素衍生物的溶液中。
2.权利要求1中的方法,其中将含有度卡霉素衍生物及糖的溶液冷冻干燥。
3.权利要求2的方法,其中溶液也含有选自电解质、水溶性聚合物、多羟基醇及表面活性剂中至少一种化合物。
5.权利要求4中的冻干药用组合物,其中在冻干之前溶液中含度卡霉素衍生物和醇。
6.权利要求5的冻干药用组合物,其中在冻干之前溶液中也含有选自电解质、水溶性聚合物、多羟基醇和表面活性剂中至少一种化合物。
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US5084468A (en) * | 1988-08-11 | 1992-01-28 | Kyowa Hakko Kogyo Co., Ltd. | Dc-88a derivatives |
JP2510335B2 (ja) * | 1989-07-03 | 1996-06-26 | 協和醗酵工業株式会社 | Dc―88a誘導体 |
KR910014122A (ko) * | 1990-01-19 | 1991-08-31 | 디께다 가즈히꼬 | 에토포시드-2-디메틸아미노 화합물의 동결건조 제제 |
US5214065A (en) * | 1990-06-11 | 1993-05-25 | Kyowa Hakko Kogyo Co., Ltd. | Dc-89 derivatives |
JPH0669954B2 (ja) * | 1990-12-07 | 1994-09-07 | 吉富製薬株式会社 | 抗腫瘍組成物 |
EP0499130A1 (en) * | 1991-02-15 | 1992-08-19 | Kyowa Hakko Kogyo Co., Ltd. | DC-89 derivatives |
JP3608802B2 (ja) * | 1991-09-20 | 2005-01-12 | 第一サントリーファーマ株式会社 | 安定なカルシトニン医薬組成物及びその製造法 |
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1994
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- 1995-05-19 US US08/737,145 patent/US5703080A/en not_active Expired - Fee Related
- 1995-05-19 WO PCT/JP1995/000962 patent/WO1995031971A1/en active IP Right Grant
- 1995-05-19 DE DE69519667T patent/DE69519667T2/de not_active Expired - Fee Related
- 1995-05-19 HU HU9603521A patent/HUT78072A/hu unknown
- 1995-05-19 PL PL95317229A patent/PL317229A1/xx unknown
- 1995-05-19 NZ NZ285450A patent/NZ285450A/en unknown
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- 1995-05-19 EP EP95918749A patent/EP0754030B1/en not_active Expired - Lifetime
- 1995-05-19 SK SK1484-96A patent/SK148496A3/sk unknown
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- 1995-05-19 BR BR9507640A patent/BR9507640A/pt not_active Application Discontinuation
- 1995-05-19 CN CN95193164A patent/CN1148805A/zh active Pending
- 1995-05-19 AT AT95918749T patent/ATE198149T1/de not_active IP Right Cessation
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1996
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- 1996-11-19 FI FI964624A patent/FI964624A/fi unknown
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BR9507640A (pt) | 1997-08-19 |
NO964813D0 (no) | 1996-11-13 |
NZ285450A (en) | 1997-02-24 |
US5703080A (en) | 1997-12-30 |
MX9605694A (es) | 1998-05-31 |
JPH07309761A (ja) | 1995-11-28 |
WO1995031971A1 (en) | 1995-11-30 |
PL317229A1 (en) | 1997-03-17 |
FI964624A0 (fi) | 1996-11-19 |
EP0754030B1 (en) | 2000-12-20 |
SK148496A3 (en) | 1997-06-04 |
CA2190635A1 (en) | 1995-11-30 |
DE69519667D1 (de) | 2001-01-25 |
FI964624A (fi) | 1996-11-19 |
HUT78072A (hu) | 1999-08-30 |
CZ338696A3 (en) | 1997-05-14 |
DE69519667T2 (de) | 2001-04-26 |
ATE198149T1 (de) | 2001-01-15 |
NO964813L (no) | 1996-11-13 |
AU2455195A (en) | 1995-12-18 |
HU9603521D0 (en) | 1997-03-28 |
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