CN1050503A - 稳定白细胞干扰素的方法 - Google Patents
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Abstract
本文介绍用二糖和任意胆汁酸或胆汁酸衍生物
处理人的干扰素,使之达到稳定状态。
Description
本发明涉及用二糖和任意胆汁酸或胆汁酸衍生物使白细胞干扰素(IFN-α),特别是冻干型IFN-α稳定化的方法。
对IFN-α可以理解为具有抗病毒和免疫调节活性的体特异性蛋白。就抗病毒感染的意义而言,其抗病毒作用不是通过对病毒本身的直接影响,而是通过对它们的靶细胞作用达到的。除抗病毒活性之外,α-干扰素还对癌肿瘤产生具体作用,使之适用于治疗癌症,而且影响身体的免疫系统,例如,它激活巨噬细胞和NK细胞,并且增强细胞膜在免疫学上有意义的各种组分的表达。
由于DNA重组技术的出现,目前可用微生物方法大量制备IFN-α,但尽管作了最大努力,迄今尚不能从天然物质(白细胞,淋巴细胞)分离和纯化制得。
为加强临床试验,首次开拓了这一新技术,尽可能广泛地将IFN-α用于治疗,并且有可能为人们探索用活性物质进行治疗而提供足够的活性物质。
目前存在的问题是:纯IFN-α在贮存期间不够稳定,并逐渐失去生物活性。
因此,为提高IFN-α的稳定性,已使用了各种辅药。加入甘氨酸就可使IFN-α达到一定程度的稳定状态(参见Publ.PCT 申请86/00,531号和欧洲专利公开82,481号),但最好同时加入白蛋白。
在致力于使IFN-α尽可能长期保持良好的稳定状态,同时又避免应用高分子化合物(例如血清白蛋白,动物胶,葡聚糖或淀粉衍生物)的过程中,已经发现采用二糖和任意胆汁酸或胆汁酸衍生物是成功的。
因此,本发明涉及一些组合物,尤以冻干型为最佳,该组合物含有二糖和任意胆汁酸或胆汁酸衍生物;以及涉及组合物的制备方法,该方法包括用二糖和任意胆汁酸或胆汁酸衍生物处理IFN-α溶液,必要时将所得溶液冻干;本发明还涉及以本发明组合物为主的药物制剂,以及二糖和任意胆汁酸或胆汁酸衍生物在IFN-α的稳定化方面的应用。
本发明组合物可用于制备防治大量感染和免疫调节异常(尤其是瘤)的药物制剂。
稳定化作用可适用于天然或重组体IFN-α(γ-IFN-α)。重组体IFN-αA(γ-IFN-αA)是本发明特别优选的IFN-α。本发明组合物中IFN-α含量并不严格要求,其浓度范围超过10的倍率,并且主要仅受IFN-α溶解度上限的限制。在人IFN-α情况下,可考虑的浓度高达5×108国际单位(I.U.)/ml,优选为0.1×106至1×108I.U./ml,最好为1×106至5×107I.U./ml。
将二糖(最好为乳糖或蔗糖)加到浓度为0.5%至15%(重量/体积),最好为5%(重量/体积)的IFN-α溶液中。
胆汁酸或胆汁酸衍生物可以是,例如,胆酸,脱氧胆酸,甘氨脱氧胆酸,牛磺脱氧胆酸,鹅脱氧胆酸,甘氨鹅脱氧胆酸,牛磺鹅脱氧胆酸,甘氨胆酸和牛磺胆酸。其中,以甘氨胆酸为最佳。将其加到浓度为0.01至3%(重量/体积),最好为0.5%(重量/体积)的IFN-α溶液中。
还可加入其它辅药,例如,pH调节剂(如氢氧化钠),pH缓冲剂(如磷酸盐缓冲剂和柠檬酸缓冲剂),等渗剂(如氯化钠)和防腐剂(如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯),以及加固冻干组织的试剂(如甘氢酸)。
下面实施例详述本发明内容。
按照文献中所述的已知方法或本技术领域人员熟知的方法,可以得到实施例中所用的纯γ-IFN-αA。
为测定γ-IFN-αA的抗病毒活性,用Madison Darby牛肾脏MDBK细胞和VSV(水疱性口炎病毒)病毒进行细胞病理学的试验,已由Rubinstein等人作过介绍〔参见J.Virol.37,755-758(1981)〕。MDBK细胞和VSV病毒一般容易得到和能够得到,例如,可由美国标准菌库(ATCC)(MDBK:ATCC Nos.CCL21和CRL6071:VSV:ATCC No.VR-1 59)得到。
研究稳定性试验时,将含γ-IFN-αA和添加剂的溶液于不同温度(5℃,25℃,35℃,45℃,55℃和65℃)下冻干和贮存。经预定的时间后,测定仍在冻干物中存在的IFN-α的抗病毒活性。
下面实施例是为了说明本发明而非限制本发明。
实施例1
将3百万I.U.的γ-IFN-αA溶于1ml含有人血清白蛋白、甘氨酸或乳糖和其它任意辅药(参见表1)的水中,所得溶液经无菌过滤(隔膜过滤器,孔径为0.2μm),装入10ml玻璃小瓶中,然后放在经蒸汽消毒的冰冻干燥器内。该溶液于-40℃冰冻4小时后,在压力为0.1mbar、约-30℃下进行真空冻干法的初级干燥14小时,接着在全真空、+20℃下进行第二级干燥4小时,充氮下,在冰冻干燥器内,用合适的铝盖封闭玻璃小瓶,接着进行各种稳定性试验。试验结果列于表1。
表1 含γ-IFN-αA的冻干组合物
冻干物成分 1 2 3 4 5
γ-IFN-αA(百万I.U.) 3.0 3.0 3.0 3.0 3.0
氯化钠(mg) 9.0 - - - -
人血清白蛋白(mg) 5.0 - - - -
无致热质甘露糖醇(mg) - - - - 20.0
甘氨酸(mg) - 20.0 - 10.0 -
乳糖(mg) - - 50.0 - -
NaH2PO4.H2O加至pH7.4 - 适量 - - 适量
NaOH IN加至pH7.4 - - 适量 适量 -
注射用水 1.0ml 1.0ml 1.0ml 1.0ml 1.0ml
抗病毒活性(百万I.U.)
制成冻干制品后 3.0 3.0 2.7 3.3 2.3
2周后/5℃ 3.2 3.0 2.8 3.3 1.8
2周后/25℃ 3.2 2.7 3.4 3.1 1.5
2周后/35℃ 3.3 2.8 3.3 2.7 1.2
2周后/45℃ 2.7 2.0 3.0 2.9 0.9
2周后/55℃ 2.8 1.5 2.4 2.1 0.8
2周后/65℃ 2.1 0.6 - - 0.4
3个月后/5℃ 2.7 2.5 3.0 3.6 -
3个月后/25℃ 2.5 2.3 3.1 3.2 -
3个月后/35℃ 2.4 2.1 3.1 2.7 -
3个月后/45℃ 1.7 1.2 2.8 1.3 -
6个月后/5℃ 3.5 3.1 3.2 3.1 -
6个月后/25℃ 3.3 3.1 3.2 2.4 -
6个月后/35℃ 2.6 1.9 3.0 2.4 -
6个月后/45℃ 未测 1.7 3.0 1.1 -
12个月后/5℃ 3.7 未测 3.0 2.8 -
12个月后/25℃ 2.9 未测 2.9 2.5 -
12个月后/35℃ 2.1 未测 2.7 1.3 -
12个月后/45℃ 未测 未测 2.7 1.6 -
含乳糖的冻干物能达到最佳结果(见第3栏)。该制剂甚至在贮藏温度为45℃下,长期保存后仍显示出极好的稳定性,这对IFN-α来说,几乎是最高贮藏温度。这一结果还可进一步明确证实含1百万I.U.γ-IFN-αA的冻干试验(见表2)。
表2 含γ-IFN-αA的冻干组合物
1 2
冻干物成分
γ-IFN-αA(百万I.U.) 0.5 0.5
甘氨酸(mg) 10.0 -
乳糖(mg) - 50.0
NaOH IN加至pH7.4 适量 适量
注射用水 1.0ml 1.0ml
抗病毒活性(百万I.U.)
制成冻干制品后 0.4 0.4
2周后/5℃ 0.5 0.4
2周后/25℃ 0.4 0.4
2周后/35℃ 0.4 0.4
2周后/45℃ 0.3 0.3
2周后/65℃ 0.2 0.3
3个月后/5℃ 0.5 0.5
3个月后/25℃ 0.4 0.4
3个月后/35℃ 0.3 0.4
3个月后/45℃ 0.2 0.4
6个月后/5℃ 0.4 0.5
6个月后/25℃ 0.4 0.4
6个月后/35℃ 0.2 0.4
6个月后/45℃ 0.05 0.3
实施例2
按类似于实施例1的方法,进行含γ-IFN-αA和蔗糖真冻干物的稳定性试验。证实了用乳糖得到的γ-IFN-αA的稳定性,也可用蔗糖使其稳定(见表3)。
表3 含γ-IFN-αA的冻干组合物
1 2 3
冻干物成分
γ-IFN-αA(百万I.U.) 3 3 3
氯化钠(mg) 9.0 - -
人血清白蛋白 5.0 - -
甘氨酸 - 20.0 10.0
蔗糖(mg) - - 50.0
NaH2PO4H2O加至pH7.4 - 适量 -
NaOH IN加至pH7.4 - - 适量
注射用水加至 1.0ml 1.0ml 1.0ml
抗病毒活性(百万I.U.)
制成冻干制品后 2.7 3.0 3.4
3个月后/5℃ 2.7 2.5 3.9
3个月后/25℃ 2.5 2.3 3.6
3个月后/35℃ 2.4 2.1 3.7
3个月后/45℃ 1.7 1.2 -
6个月后/5℃ 3.5 3.1 4.0
6个月后/25℃ 3.3 3.1 3.7
6个月后/35℃ 2.6 1.9 3.7
6个月后/45℃ - 1.7 -
实施例3
按类似于实施例1的方法,进行含高浓度γ-IFN-αA和乳糖或蔗糖冻干物的稳定性试验。证实了用二糖产生的IFN-α的稳定性,也适用于高浓度γ-IFN-αA(见表4)。
表4 含γ-IFN-αA的冻干组合物
冻干物成分 1 2 3 4
γ-IFN-αA(百万I.U.) 9.0 9.0 18.0 18.0
乳糖 50.0mg - 50.0mg -
蔗糖 - 50.0mg - 50.0mg
甘氨酸 10.0mg 10.0mg 10.0mg 10.0mg
NaOH IN加至pH7.4 - - - q.s.
注射用水加至 1.0ml 1.0ml 1.0ml 1.0ml
抗病毒活性(百万I.U.)
制成冻干制品后 8.8 8.9 18.3 19.9
3个月后/5℃ 9.9 9.6 17.8 23.4
3个月后/25℃ 10.0 10.5 19.1 23.2
3个月后/35℃ 10.3 10.1 20.5 未测
3个月后/45℃ 10.4 10.9 22.0 未测
6个月后/5℃ 9.7 未测 17.8 19.1
6个月后/25℃ 8.9 未测 21.1 21.9
6个月后/35℃ 8.9 未测. 16.6 未测
6个月后/45℃ 8.4. 未测. 16.1 未测
实施例4
按类似于实施例1的方法,进行含γ-IFN-αA、乳糖和甘氨胆酸冻干物的稳定性试验。试验结果列于表5。
表5 含γ-IFN-αA的真空冻干组合物
冻干物组分:
γ-IFN-αA(百万I.U.) 1 3 9 18
甘氨胆酸(mg) 5.0 5.0 5.0 5.0
乳糖(mg) 50.0 50.0 50.0 50.0
氯化钠(mg) 2.5 2.5 2.5 2.5
NaOH IN加至pH7.4 适量 适量 适量 适量
注射用水加至 1.0ml 1.0ml 1.0ml 1.0ml
抗病毒活性(百万I.U.)
制成冻干制品后 0.96 2.97 8.56 18.8
14天后/5℃ 0.85 - - -
14天后/室温 0.92 - - -
14天后/35℃ 0.85 - - -
14天后/45℃ 0.83 - -
6个月后/5℃ 1.02 2.89 9.2 18.7
6个月后/室温 1.1 2.82 8.7 18.7
6个月后/35℃ 1.06 3.11 8.9 18.3
6个月后/45℃ 0.99 2.71 8.94 未测
Claims (13)
1、一种制备含α-干扰素、二糖和任意胆汁酸或胆汁酸衍生物的组合物的方法,其特征在于用二糖和任意胆汁酸或胆汁酸衍生物处理α-干扰素,最好用甘氨胆酸处理,必要时,将所得溶液冻干。
2、按权利要求1的方法,其特征在于采用天然或重组体人的白细胞干扰素,最好为γ-IFN-αA。
3、按权利要求1或2的方法,其特征在于采用浓度为0.5%至15%(重量/体积),最好为5%(重量/体积)的乳糖或蔗糖。
4、按权利要求1-3的方法,其特征在于采用浓度为0.1%至3.0%(重量/体积)的胆汁酸或胆汁酸衍生物,最好是浓度为0.1%到1%(重量/体积)的甘氨胆酸。
5、按权利要求4的方法,其特征在于采用浓度为0.5%(重量/体积)的胆汁酸衍生物,最好是浓度为0.5%(重量/体积)的甘氨胆酸。
6、按权利要求1的方法,其特征在于采用γ-IFN-αA,5%(重量/体积)乳糖和0.5%(重量/体积)甘氨胆酸。
7、按权利要求1-6中任一项所述方法制得的组合物为基础的药物制剂。
8、二糖最好是浓度为0.5%至15%(重量/体积)的乳糖或蔗糖和任意的胆汁酸或胆汁酸衍生物,最好是浓度为0.1%至1%(重量/体积)的甘氨胆酸用于α-干扰素的稳定化。
9、按权利要求1-6之任一项所述方法制得的组合物用于制备预防或治疗免疫调节异常的药物制剂。
10、按权利要求1-6之任一项所述方法制得的组合物用于制备防治病毒感染的药物制剂。
11、按权利要求1-6之任一项所述方法制得的组合物用于制备防治免疫调节异常的药物制剂。
12、按权利要求1-6之任一项所述方法制得的组合物用于制备防治瘤的药物制剂。
13、按权利要求1-6之任一项所述方法制备的含α-干扰素、二糖和任意胆汁酸或胆汁酸衍生物的组合物。
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EP (1) | EP0420049B1 (zh) |
JP (1) | JPH03130232A (zh) |
KR (1) | KR910005886A (zh) |
CN (1) | CN1050503A (zh) |
AR (1) | AR244551A1 (zh) |
AT (1) | ATE92334T1 (zh) |
AU (1) | AU636653B2 (zh) |
CA (1) | CA2024046A1 (zh) |
CZ (1) | CZ277712B6 (zh) |
DD (1) | DD298054A5 (zh) |
DE (1) | DE59002183D1 (zh) |
FI (1) | FI904756A0 (zh) |
HU (1) | HU205555B (zh) |
IE (1) | IE903479A1 (zh) |
IL (1) | IL95769A0 (zh) |
IS (1) | IS3631A7 (zh) |
MC (1) | MC2149A1 (zh) |
MX (1) | MX22522A (zh) |
MY (1) | MY106615A (zh) |
NO (1) | NO904218L (zh) |
NZ (1) | NZ235153A (zh) |
PH (1) | PH27531A (zh) |
PT (1) | PT95454A (zh) |
RU (1) | RU2008017C1 (zh) |
YU (1) | YU184090A (zh) |
ZA (1) | ZA907579B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001041793A1 (fr) * | 1999-12-06 | 2001-06-14 | Tianjin Hualida Bioengineering Co., Ltd. | Formulation stable d'interferon en solution, son procede de preparation et ses applications |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6794194A (en) * | 1993-05-18 | 1994-12-20 | Bukh Meditec A/S | A method for the preparation of interferons |
DE69715883T2 (de) * | 1996-05-09 | 2003-07-31 | Feronpatent Ltd., Gibraltar | Stabilisierung von interferonen in wässriger lösung durch gummiarabikum |
WO1998051328A1 (en) * | 1997-05-09 | 1998-11-19 | Feronpatent Limited | Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets |
US6180096B1 (en) | 1998-03-26 | 2001-01-30 | Schering Corporation | Formulations for protection of peg-interferon alpha conjugates |
PT1066059E (pt) * | 1998-03-26 | 2005-10-31 | Schering Corp | Formulacoes para proteccao de conjugados de peg-interferao alfa |
US7632491B2 (en) | 2004-08-12 | 2009-12-15 | Schering Corporation | Stable pegylated interferon formulation |
DE102004048379A1 (de) | 2004-10-01 | 2006-04-13 | "Stiftung Caesar" (Center Of Advanced European Studies And Research) | Federelement aus gesputterter Formgedächtnis-Legierung |
CU23432B6 (es) * | 2005-11-02 | 2009-10-16 | Ct Ingenieria Genetica Biotech | Formulaciones estabilizadas que contienen a los interferones gamma y alfa en proporciones potenciadoras |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5821691A (ja) * | 1981-07-29 | 1983-02-08 | Mochida Pharmaceut Co Ltd | α−及びβ−インタ−フェロンの精製方法 |
EP0080879B1 (en) * | 1981-11-28 | 1986-10-01 | Sunstar Kabushiki Kaisha | Pharmaceutical composition containing interferon in stable state |
EP0124018B1 (en) * | 1983-04-28 | 1987-11-25 | Armour Pharmaceutical Company | Pharmaceutical preparation containing purified fibronectin |
EP0133767B1 (en) * | 1983-08-04 | 1991-04-03 | The Green Cross Corporation | Gamma interferon composition |
IL78231A (en) * | 1985-03-25 | 1990-07-26 | Schering Corp | Stable gamma-interferon formulation |
US4816568A (en) * | 1986-05-16 | 1989-03-28 | International Minerals & Chemical Corp. | Stabilization of growth hormones |
-
1990
- 1990-08-27 CA CA002024046A patent/CA2024046A1/en not_active Abandoned
- 1990-09-03 NZ NZ235153A patent/NZ235153A/en unknown
- 1990-09-06 CZ CS904328A patent/CZ277712B6/cs unknown
- 1990-09-20 EP EP90118132A patent/EP0420049B1/de not_active Expired - Lifetime
- 1990-09-20 AT AT90118132T patent/ATE92334T1/de not_active IP Right Cessation
- 1990-09-20 DE DE9090118132T patent/DE59002183D1/de not_active Expired - Fee Related
- 1990-09-21 AU AU63098/90A patent/AU636653B2/en not_active Expired - Fee Related
- 1990-09-21 ZA ZA907579A patent/ZA907579B/xx unknown
- 1990-09-24 MC MC902149A patent/MC2149A1/xx unknown
- 1990-09-24 MX MX2252290A patent/MX22522A/es unknown
- 1990-09-24 HU HU906021A patent/HU205555B/hu not_active IP Right Cessation
- 1990-09-25 IL IL95769A patent/IL95769A0/xx unknown
- 1990-09-26 AR AR90317958A patent/AR244551A1/es active
- 1990-09-26 PH PH41267A patent/PH27531A/en unknown
- 1990-09-26 DD DD90344228A patent/DD298054A5/de not_active IP Right Cessation
- 1990-09-26 MY MYPI90001656A patent/MY106615A/en unknown
- 1990-09-27 JP JP2258806A patent/JPH03130232A/ja active Pending
- 1990-09-27 KR KR1019900015368A patent/KR910005886A/ko not_active Application Discontinuation
- 1990-09-27 FI FI904756A patent/FI904756A0/fi not_active IP Right Cessation
- 1990-09-27 NO NO90904218A patent/NO904218L/no unknown
- 1990-09-27 IS IS3631A patent/IS3631A7/is unknown
- 1990-09-27 RU SU904831274A patent/RU2008017C1/ru active
- 1990-09-27 CN CN90108133A patent/CN1050503A/zh active Pending
- 1990-09-27 PT PT95454A patent/PT95454A/pt not_active Application Discontinuation
- 1990-09-27 IE IE347990A patent/IE903479A1/en unknown
- 1990-09-28 YU YU184090A patent/YU184090A/sh unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001041793A1 (fr) * | 1999-12-06 | 2001-06-14 | Tianjin Hualida Bioengineering Co., Ltd. | Formulation stable d'interferon en solution, son procede de preparation et ses applications |
Also Published As
Publication number | Publication date |
---|---|
EP0420049B1 (de) | 1993-08-04 |
HU906021D0 (en) | 1991-03-28 |
AU636653B2 (en) | 1993-05-06 |
MY106615A (en) | 1995-06-30 |
AU6309890A (en) | 1991-04-11 |
DD298054A5 (de) | 1992-02-06 |
MC2149A1 (fr) | 1992-03-10 |
AR244551A1 (es) | 1993-11-30 |
PT95454A (pt) | 1991-05-22 |
NZ235153A (en) | 1993-03-26 |
CZ277712B6 (en) | 1993-03-17 |
CA2024046A1 (en) | 1991-03-29 |
YU184090A (sh) | 1992-09-07 |
HU205555B (en) | 1992-05-28 |
IE903479A1 (en) | 1991-04-10 |
IL95769A0 (en) | 1991-06-30 |
MX22522A (es) | 1993-10-01 |
ATE92334T1 (de) | 1993-08-15 |
KR910005886A (ko) | 1991-04-27 |
FI904756A0 (fi) | 1990-09-27 |
CS432890A3 (en) | 1992-12-16 |
ZA907579B (en) | 1991-06-26 |
PH27531A (en) | 1993-08-18 |
HUT56284A (en) | 1991-08-28 |
IS3631A7 (is) | 1991-03-29 |
DE59002183D1 (de) | 1993-09-09 |
NO904218D0 (no) | 1990-09-27 |
NO904218L (no) | 1991-04-02 |
EP0420049A1 (de) | 1991-04-03 |
RU2008017C1 (ru) | 1994-02-28 |
JPH03130232A (ja) | 1991-06-04 |
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