CN1200032A - 制备含有生物活性肽的植入物的方法 - Google Patents
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Abstract
一种制备用于在为期1—12个月的时间内输送有效量的生物活性肽或肽类似物的药用组合物的方法。该方法包括以下步骤:将乙交酯单位与丙交酯单位之比为大约0—5∶1的乳酸与乙醇酸的共聚物研磨成粒度大约为50—150μm;用剂量大约为1—2.5兆拉德的电离γ辐射对研磨的共聚物进行灭菌;用生物活性肽或肽类似物的无菌含水浆液润湿研磨、无菌的共聚物;在无菌条件下混合所述共聚物和浆液,以得到共聚物与大约10—50%生物活性肽或肽类似物的均匀混合物;在减压及不超过25℃的温度下干燥该混合物;在无菌条件下,于70—110℃的温度下挤压干燥的混合物;并在无菌条件下将挤压混合物切成直径约为1—2mm、长度约为10—25mm的圆柱形棒,以制成药用植入物。
Description
本发明涉及一种制备生物活性肽或肽类似物的植入物的新方法,其中,肽或肽类似物在该植入物中的分布更加均匀。
已将多种生物活性肽和肽类似物用作治疗各种疾病的活性剂。这种活性剂通常与聚合物输送系统一起使用,以控制该活性剂的释放。例如,当采用合适的输送系统长期服用天然下丘脑激素LHRH(促黄体素释放激素,一种癸肽)的肽类似物时具有治疗价值。在商业上取得了成功的输送系统包括微球体、微胶囊、微粒和其它植入物形式,当皮下或肌内注射这种植入物时,可从生物相容性并可生物降解的基质中释放出该LHRH类似物。所述基质通常为乳酸和乙醇酸的共聚物(“PLGA”,聚乳酸乙醇酸),如在美国专利3,773,919,3,887,499,4,675,189,4,767,628和很多其它美国专利中所述的。
一直以为,所述生物活性剂的连续或单相释放是上述制剂的十分理想的特征(例如,参见美国专利5,366,734)。事实上,现在已经认识到,真正需要的是在一段较长时期内(例如,3-6个月或更长时间)维持或保持所述肽或肽类似物的“治疗”效果。因此,希望而且需要在此方面加以改进。
本发明涉及一种制备用于在为期1-12个月的时间内输送有效量的生物活性肽或肽类似物的药用植入物的方法,该方法包括:将乙交酯单位与丙交酯单位之比大约为0-5∶1的乳酸和乙醇酸的共聚物研磨至粒度大约为50-150μm;用一种生物活性肽或肽类似物的含水浆液润湿研碎的共聚物;混合该共聚物和浆液,以得到该共聚物与大约10-50%生物活性肽的均匀混合物;在减压及不超过25℃的温度下干燥该混合物;在大约70-110℃的温度下挤压干燥的混合物;将挤压的混合物切成直径约为1-2mm、长度约为25mm的圆柱形棒,以制成植入物。
有利地是,在与生物活性肽混合之前用剂量约为1-2.5兆拉德的电离γ-辐射对研碎的共聚物进行灭菌,而且,混合、挤压和切割步骤均在无菌条件下进行。另外,在给治疗对象或患者施用之前,通常要以常规方法对植入物进行灭菌。
由所述聚合物或共聚物形成一种可生物降解的基质,其中含有均匀分布的肽或肽类似物。在该共聚物中,乙交酯单位与丙交酯单位的优选比例为大约0.5∶1-3∶1。一种特别优选使用的共聚物可溶于苯,而且具有0.51-1的比浓对数粘度(1%,于苯中)。最好控制浆液的量,以使混合物中水的量大约为35-65ml/100克共聚物,使所述棒中生物活性肽的量为大约10-50%(重量)。
所述生物活性肽或肽类似物可以是LHRH、GnRH、生长激素释放激素、生长激素释放肽、血管紧张肽、铃蟾肽、缓激肽、缩胆囊肽、脑啡肽、神经激肽、速激肽或P物质的兴奋剂或拮抗剂。所述生物活性肽还可以是一种抑制剂,如肾素抑制剂、蛋白酶抑制剂、金属肽酶抑制剂、脑啡肽酶和心钠素或脑钠素降解酶抑制剂。LHRH类似物优选为LHRH兴奋剂或拮抗剂的药用盐,如以下化合物的药用盐:leuprolide、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)、布舍瑞林(buserelin)、avorelin、deslorelin、组氨瑞林(histrelin)、cetrorelix、teverelix、ramorelix、抗排卵肽(antide)、nictide、azaline B、azaline C或ganirelix。
本发明的另一方面涉及按照本发明的方法获得的药用植入物。该植入物优选装在带有伸缩式针头的植入器械中,使其适于在哺乳动物的皮下进行皮下注射。
图1是在注射本发明例1的avorelin植入物180天之后雄性比哥猎狗的血清睾酮含量和血浆avorelin含量的曲线图;和
图2和3是在注射本发明例2和3的avorelin植入物达33-35周内,雄性患者的血清LH、FSH和睾酮含量的曲线图。
任何聚丙交酯聚合物或PLGA共聚物均可用于制备本发明的可生物降解的基质。这类材料为本领域普通技术人员所熟知,例如,可参见上述美国专利,因而无须进一步说明。选择特定的共聚物,然后将其研磨至粒度大约为50-150μm。该研磨步骤也是常见的,无须进一步解释。
在最佳方法中,同样是用本领域普通技术人员所公知的传统方法用剂量大约为1-2.5兆拉德的电离γ-辐射对研碎的共聚物进行灭菌。
然后用生物活性肽或肽类似物活性剂的无菌含水浆液润湿上述研碎的无菌共聚物颗粒。该浆液是通过在无菌水中混合所述肽、类似物、或其药用盐而制成的。活性剂的用量可以在很大范围内波动,例如,大约为5-50克/升,优选约为10-25克/升。然后用传统方法对该溶液进行灭菌,例如,通过灭菌滤器灭菌。如果必要,可以浓缩该溶液,以提高其中肽或肽类似物的量。可以改变该溶液中肽或肽类似物的浓度,以改变所得植入物的剂量。
然后,在无菌条件下混合该共聚物和浆液,以得到共聚物与活性剂的均匀混合物。根据需要的制剂,活性剂占该混合物的大约10-50%,优选约为15-25%。如上所述,该混合物中含水量约为35-65ml/100克共聚物是理想的,优选约为45-55ml/100克共聚物。接着,在减压及不超过25℃的温度下干燥该混合物,以制成药用组合物。如果需要,可以用常见载体将该组合物制备成用于注射的浆液。
另外,可以用传统挤压设备在大约70-110℃的温度下将干燥的组合物挤压成“圆条面”状或连续的棒状制品。在挤压步骤中加热,有助于进一步干燥该制品。为了制备植入物,在无菌条件下将该挤压混合物的圆柱形棒切成直径大约为1-2mm,长度约为10-25mm的条。植入物的长度是改变其中生物活性肽或肽类似物剂量的另一种因素。然后可以用常见的植入器械将该制品植入患者的皮下。
本发明提供了一种有效释放(即:就治疗效果而言)生物活性肽或肽类似物,如LHRH类似物的方法,即使在这种释放方法中测得的该肽或肽类似物的血浆含量是间断的或不连续的。例如,在暴露于自身长效的LHRH兴奋剂或LHRH拮抗剂后,通过脑垂体受体的内化或下调可取得上述效果。
本发明方法可用于多种肽或肽类似物。除了本文提到的LHRH类似物之外,还有GnRH或生长激素释放激素或肽。一般,从治疗角度看,需要在工艺条件下化学稳定的并且能持续释放的任何肽或肽类似物。这种肽或肽类似物的非限定性例子有:抑生长素和抑生长素类似物,血管紧张肽II的兴奋剂和拮抗剂,铃蟾肽类似物、优选铃蟾肽拮抗剂,缓激肽拮抗剂、优选具有最低组胺释放特性,缩胆囊肽类似物、优选缩胆囊肽拮抗剂,脑啡肽类似物、神经激肽、速激肽和P物质拮抗剂、肾素抑制剂和其它天冬氨酰蛋白酶抑制剂如HIV蛋白酶抑制剂、金属肽酶抑制剂如血管紧张肽转化酶、脑啡肽酶和心钠素或脑钠素降解酶抑制剂。本领域技术人员优选那些动物和人不能或很难通过口服途径吸收的肽或肽模似化合物,并会根据该化合物的生物学效力、每日所需的有效剂量和该制剂的估计持续释放时间调整其在本发明植入物中的制备剂量。
本发明还消除了有机溶剂,特别是氯化溶剂,如三氯甲烷或二氯甲烷对所述制剂的污染,这种溶剂通常被用于通过凝聚-溶剂蒸发方法(例如,参见US 3,773,919)制备微球体或微胶囊,或用于通过过滤对PLGA共聚物进行灭菌。
本发明不使用任何有机溶剂,而是采用了不常使用的水,一种迄今为止被视为不适用于该制剂的溶剂,因为它对PLGA基质的聚酯(共聚物)具有损害作用,其中,它能够加速化学水解作用,并会在出于安全考虑的灭菌步骤中进行电离辐射时破坏结构完整性(形成自由基)。
水的这种非惯例使用的另一个优点是,实现了活性成分在粒化聚合物粉上的均匀涂覆,获得了该混合物更必要的、更理想的均匀性,这是该制备方法的一个必要条件。该非常规溶剂的另一个意外的优点是粉状混合物的“可湿性”,否则会因为静电荷的产生而出现严重问题,这会导致不能接受的机械损失和均匀性损失。
本发明的方法还提供了一种通过在混合所述聚合物与生物活性肽或肽类似物之前对该聚合物进行电离辐射而对所述组合物进行灭菌的简单方法,否则,所述生物活性肽或肽类似物会不可避免地受到辐射的损害,产生不希望的副产品。本发明方法的另一个优点是,提供了一种由共聚物中存在的实际生物量预定的可变辐射灭菌剂量(1-2.5兆拉德),因而具有不会过分产生辐射分解现象的安全性。
实施例
提供以下实施例是为了说明本发明最佳制剂的效果。例1
制备工艺是在装有气锁(air-locks)的商购分离器(ARFL,Neuilly-sur-Marne,法国)上完成的,所述气锁用于引入预先灭过菌的成分,而该装置本身预先用过乙酸处理进行灭菌。挤压机是一台装有压力和温度探测器的商购单螺旋挤压机(Brabender,47055Duisburg,Germany)。切割机械是商购的(Davis-Standard Corp.CedarGrove,N.J.,USA)。混合器/搅拌器及称重仪均为常规设备。
将80g可溶于苯的、比浓对数粘度为0.60(以1%的浓度溶于苯中)的乳酸与乙醇酸(75∶25)的外消旋共聚物(PuracBiochemB.V.,Gorinchem,Netherlands)研碎并过筛,收集50-150μm的颗粒级分,用商用实验设备(Caric-Mediris,Fleurus,Belgium)以1.5兆拉德的剂量进行电离γ-辐射灭菌,并经气锁引入无菌分离器中。
另外,将23g LHRH类似物,乙酸avorelin(INN)或乙酸(2Methyl-D-Trp)6(des-Gly)10(ProEthylamide)9LHRH溶于500ml无菌水中,并经过Millipore 0.2μm灭菌滤器过滤。通过蒸发将无菌溶液减少至体积为50ml,并将所得混合物分散在研磨过的共聚物中。混合润湿的混合物,以获得含有20%avorelin的颗粒。25℃的减压条件下干燥该混合物,然后在3500p.s.i.的压力下,在70-110℃的温度梯度内挤压干燥过的混合物。在无菌条件下将该挤出物切成直径为1.5mm,长度为15mm的棒,其含有10mg avorelin,将这种棒插入预先灭菌的带有伸缩式针头的植入器(SFM GmbH,D-6480Wchtersbach,Germany)中,密封并原样使用,或者在临床应用之前以1.5兆拉德的γ-辐射剂量任选地进行进一步灭菌。
在以皮下(s.c.)方式植入雄性比哥猎狗体内时,在开始LH和睾酮刺激后,睾酮的阉割含量维持6个月。avorelin的血浆含量在短期爆发后,在第40天降至最低水平,并在第120天再次升高,然后在第160天变得不能测出。结果如图1所示。
例2
大致按例1方法制备10mg avorelin植入物,进一步灭菌并植入健康的男性患者体内。在开始LH、FSH和睾酮刺激后,其含量明显降低,睾酮含量维持低于阉割水平33周时间。结果如图2所示。
例3
大致按例2方法制备植入物,不同的是加大植入物的长度,制备成剂量为15mg的avorelin植入物。对该植入物进行灭菌,并植入健康的男性患者体内。在开始LH、FSH和睾酮刺激之后,其含量显著降低,维持睾酮含量低于阉割水平33周时间。结果如图3所示。
例4
大致按例1方法制备含有22mg leuprolide、10mg戈舍瑞林和30mg teverelix的棒,根据特定的LHRH类似物,需要对例1方法加以适当改进。
Claims (12)
1.一种制备用于在为期1-12个月的时间内输送有效量的生物活性肽或肽类似物的药用植入物的方法,该方法包括:
将乙交酯单位与丙交酯单位之比约为0-5∶1的乳酸和乙醇酸的共聚物研磨成粒度大约为50-150μm;
用生物活性肽或肽类似物的无菌含水浆液润湿所述研碎的无菌共聚物;
混合所述共聚物和浆液,以获得所述共聚物与大约10-50%生物活性肽或肽类似物的均匀混合物;
在减压及不超过25℃的温度下干燥所述混合物;
在大约70-110℃的温度下挤压所述干燥的混合物;和
将挤压的混合物切成直径约为1-2mm、长度约为10-25mm的圆柱形棒,以制成药用植入物。
2.如权利要求1的方法,还包括在加入含水浆液之前用剂量约为1-2.5兆拉德的电离γ-辐射对所述研碎的共聚物进行灭菌。
3.如权利要求1的方法,它还包括在无菌条件下完成所述混合、挤压和切割步骤。
4.如权利要求1的方法,还包括选择待用的共聚物,该共聚物可溶于苯而且比浓对数粘度为0.51-1(1%,于苯中)。
5.如权利要求1的方法,其中,对浆液的量加以控制,使所述混合物中的水量为大约35-65ml/100克共聚物。
6.如权利要求1的方法,其中,对浆液的量加以控制,使所述棒中生物活性肽或肽类似物的量大约为10-50wt%。
7.如权利要求1的方法,其中,所述共聚物中乙交酯与丙交酯之比大约为0.5∶1-3∶1。
8.如权利要求1的方法,其中,所述生物活性肽或肽衍生物是以下物质的兴奋剂或拮抗剂:LHRH、GnRH、生长激素释放激素、生长激素释放肽、血管紧张肽、铃蟾肽、缓激肽、缩胆囊肽、脑啡肽、神经激肽、速激肽或P物质。
9.如权利要求1的方法,其中,所述生物活性肽或肽类似物是肾素抑制剂、蛋白酶抑制剂、金属肽酶抑制剂、脑啡肽酶和心钠素或脑钠素降解酶抑制剂。
10.如权利要求8的方法,其中,所述生物活性肽或肽类似物是以下物质的药用盐:leuprolide、戈舍瑞林、曲普瑞林、布舍瑞林、avorelin、deslorelin、组氨瑞林、cetrorelix、teverelix、ramorelix、抗排卵肽、nictide、azaline B、azaline C或ganirelix。
11.用上述任一项权利要求的方法获得的药用植入物。
12.如权利要求11的药用植入物,它装在带有伸缩式针头的植入器械中,适于在哺乳动物皮下进行皮下注射。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2544496P | 1996-09-04 | 1996-09-04 | |
US60/025,444 | 1996-09-04 | ||
US08/897,942 US5945128A (en) | 1996-09-04 | 1997-07-21 | Process to manufacture implants containing bioactive peptides |
US08/897,942 | 1997-07-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1200032A true CN1200032A (zh) | 1998-11-25 |
Family
ID=26699745
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN97191184A Pending CN1200032A (zh) | 1996-09-04 | 1997-07-28 | 制备含有生物活性肽的植入物的方法 |
Country Status (14)
Country | Link |
---|---|
US (3) | US5945128A (zh) |
EP (1) | EP0858323B1 (zh) |
JP (1) | JPH11514678A (zh) |
KR (1) | KR100343645B1 (zh) |
CN (1) | CN1200032A (zh) |
AT (1) | ATE262889T1 (zh) |
AU (1) | AU713123B2 (zh) |
BR (1) | BR9706741A (zh) |
CA (1) | CA2236595A1 (zh) |
DE (1) | DE69728371T2 (zh) |
DK (1) | DK0858323T3 (zh) |
ES (1) | ES2218696T3 (zh) |
PT (1) | PT858323E (zh) |
WO (1) | WO1998009613A1 (zh) |
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CN1913924B (zh) * | 2004-02-05 | 2011-11-09 | 益普生制药股份有限公司 | 包括醋酸曲普瑞林的固体缓释制剂 |
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-
1997
- 1997-07-21 US US08/897,942 patent/US5945128A/en not_active Expired - Fee Related
- 1997-07-28 EP EP97937521A patent/EP0858323B1/en not_active Expired - Lifetime
- 1997-07-28 JP JP10512154A patent/JPH11514678A/ja active Pending
- 1997-07-28 CN CN97191184A patent/CN1200032A/zh active Pending
- 1997-07-28 CA CA002236595A patent/CA2236595A1/en not_active Abandoned
- 1997-07-28 BR BR9706741A patent/BR9706741A/pt not_active IP Right Cessation
- 1997-07-28 DK DK97937521T patent/DK0858323T3/da active
- 1997-07-28 WO PCT/EP1997/004095 patent/WO1998009613A1/en active IP Right Grant
- 1997-07-28 PT PT97937521T patent/PT858323E/pt unknown
- 1997-07-28 KR KR1019980703242A patent/KR100343645B1/ko not_active IP Right Cessation
- 1997-07-28 AU AU40121/97A patent/AU713123B2/en not_active Ceased
- 1997-07-28 ES ES97937521T patent/ES2218696T3/es not_active Expired - Lifetime
- 1997-07-28 AT AT97937521T patent/ATE262889T1/de not_active IP Right Cessation
- 1997-07-28 DE DE1997628371 patent/DE69728371T2/de not_active Expired - Fee Related
-
1999
- 1999-05-14 US US09/311,744 patent/US6077523A/en not_active Expired - Fee Related
-
2000
- 2000-04-05 US US09/543,707 patent/US6159490A/en not_active Expired - Fee Related
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1913924B (zh) * | 2004-02-05 | 2011-11-09 | 益普生制药股份有限公司 | 包括醋酸曲普瑞林的固体缓释制剂 |
CN101404979B (zh) * | 2006-03-21 | 2014-04-02 | 赫素股份公司 | 包含降解抗性聚交酯聚合物和lh-rh类似物的皮下植入物 |
CN106413689A (zh) * | 2014-04-30 | 2017-02-15 | 阿西诺供应公司 | 制备药物组合物的方法和装置 |
Also Published As
Publication number | Publication date |
---|---|
US6077523A (en) | 2000-06-20 |
DE69728371T2 (de) | 2005-01-13 |
US6159490A (en) | 2000-12-12 |
AU713123B2 (en) | 1999-11-25 |
WO1998009613A1 (en) | 1998-03-12 |
KR100343645B1 (ko) | 2002-08-22 |
CA2236595A1 (en) | 1998-03-12 |
JPH11514678A (ja) | 1999-12-14 |
EP0858323B1 (en) | 2004-03-31 |
DE69728371D1 (de) | 2004-05-06 |
PT858323E (pt) | 2004-08-31 |
KR20000064317A (ko) | 2000-11-06 |
BR9706741A (pt) | 1999-07-20 |
US5945128A (en) | 1999-08-31 |
EP0858323A1 (en) | 1998-08-19 |
DK0858323T3 (da) | 2004-06-28 |
AU4012197A (en) | 1998-03-26 |
ES2218696T3 (es) | 2004-11-16 |
ATE262889T1 (de) | 2004-04-15 |
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