CN1281370A - 稳定的特立帕肽溶液 - Google Patents
稳定的特立帕肽溶液 Download PDFInfo
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- CN1281370A CN1281370A CN98811964A CN98811964A CN1281370A CN 1281370 A CN1281370 A CN 1281370A CN 98811964 A CN98811964 A CN 98811964A CN 98811964 A CN98811964 A CN 98811964A CN 1281370 A CN1281370 A CN 1281370A
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Abstract
描述了呈非肠道给药的溶液形式的甲状旁腺激素的稳定的药物组合物,其中治疗活性成分用缓冲液和多羟基化合物稳定。优选的制剂含有人PTH(1—34)水溶液、甘露醇、乙酸盐或酒石酸盐缓冲剂和作为防腐剂的m－甲酚或苯甲醇。
Description
技术领域
本发明涉及含甲状旁腺激素的药物组合物。更具体地说，本发明涉及特立帕肽(teriparatide)，PTH(1-34)的稳定的溶液制剂。
发明背景
甲状旁腺激素(PTH)是一种哺乳动物甲状旁腺分泌的，84个氨基酸的产物，其通过对多种组织包括骨的作用控制血清钙水平。某些形式的PTH对人类的研究证明其具有对骨的合成代谢作用，在将其用于治疗骨质疏松症和相关骨疾病方面引起相当明显的关注。
以牛和人激素的N-末端34个氨基酸(所有公开报道均认为其生物学上等同于全长激素)为例，已经证实，当经皮下途径以脉动方式对人给药甲状旁腺激素时，甲状旁腺激素尤其促进骨生长。已经证明，与PTH略微不同的一种形式，人PTH(1-38)具有相似的结果。
PTH制剂由新鲜或冻干激素重构，并加入各种形式的载体、赋形剂和介质。大多数在水基介质如盐水、或通常用乙酸酸化的水中制备，用于稳定激素。大多数报道的制剂还加入白蛋白作为稳定剂(参见，例如，Reeve等，英国医学杂志(Br.Med.J.)，1980，280：6228；Reeve等，柳叶刀，1976，1：1035；Reeve等，Calcif．Tissue Res.，1976，21：469；Hodsman等，Bone Miner，1990，9(2)：137；Tsai等，临床内分泌代谢杂志(J.Clin.Endocrinol Metab.)，1989，69(5)：1024；Isaac等，激素代谢研究(Horm.Metab.Res.)1980，12(9)：487；Law等，临床研究杂志(J.Clin Invest.)1983，72(3)：1106；和Hulter，J.Clin Hypertens，1986，2(4)：360)。其他报道的制剂中加入赋形剂，例如甘露醇，其存在于冻干激素中或者存在于重构介质中。应用于人类研究的代表性制剂包括：人PTH(1-34)(SEQ ID NO：2)制剂，其在重构之后，由甘露醇、热灭活的人血清白蛋白，和作为吸收增强子的己酸(蛋白酶抑制剂)组成。(参见，Reeve等，1976，Calcif.Tissue Res.，21，增刊，469-477)；人PTH(1-38)制剂，在盐水介质中重构(参见，Hodsman等，1991，14(1)，67-83)；和牛PTH(1-34)制剂，其在由乙酸调节pH的水介质中，并含有白蛋白。还有一种人PTH(1-84)(SEQ ID NO：1)的国际参照制剂，其由100ng与250μg人血清白蛋白偶联的激素和1.25mg乳糖组成(1981)，以及牛PTH(1-84)，其由0.01M乙酸中的10μg冻干激素和0.1％w/v甘露醇组成(参见Martindale，附加药典(The Extra Pharmacoepia)，药学出版社，伦敦，第29版，1989，1338页)。
近来在改进h-PTH(1-34)(SEQ ID NO：2)的冻干制剂稳定性的尝试中，在在EP619119中报道了将其与糖和氯化钠组合。美国专利5496801也描述了一种天然激素，PTH(1-84)的冷东干燥组合物，其中含有甘露醇作为赋形剂和柠檬酸盐源作为不挥发性缓冲剂。
甲状旁腺激素的商业开发需要研制一种在储藏稳定性和易于制备方面可接受的制剂。因为它是一种蛋白质，因此与传统小分子量药物相比非常不稳定，然而，甲状旁腺激素制剂面临着制药工业不常遇到的挑战。而且，象其它已经成功地配制的蛋白质一样，PTH对氧化、脱酰胺基和水解尤其敏感，需要其N-末端和C-末端序列保持完整，以便保留生物活性。
本发明的一个目的在于提供一种药用的PTH制剂，特别是含有作为活性成分的特立帕肽，PTH(1-34)(SEQ ID NO：2)的PTH制剂。
发明概述
本发明提供了一种稳定溶液形式的药物组合物，其中含有治疗有效量的甲状旁腺激素(PTH)。该溶液储藏稳定，可以以无菌形式储藏于小瓶或药筒中，用于对人类患者非肠道给药。本发明溶液的优点在于不需要冷东干燥。
因此，本发明为一种甲状旁腺激素溶液，包括：
(a) 治疗有效量的甲状旁腺激素；
(b) 有效量的稳定剂；
(c) 含量足以维持组合物的pH在约3-7范围内的缓冲剂；和
(d) 余量的水。
该溶液可以，如果需要，进行冷冻干燥，以形成含不超过2％重量水的冷冻干燥粉末。
本发明的另一方面为一种甲状旁腺激素溶液，包括：
(a) 治疗有效量的甲状旁腺激素；
(b) 约1-20 wt％的稳定剂；
(c) 含量足以维持组合物的pH在约3-7范围内的缓冲剂，其选自乙酸盐或酒石酸盐源；
(d) 约0.1-2 wt％的非肠道可接受的防腐剂；和
(e) 余量的水。
本发明的再一方面为一种重构之前的冷冻干燥粉末形式的药物组合物，包括：
(a) 治疗有效量的甲状旁腺激素片段，选自PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)；
(b) 有效量的稳定剂；
(c) 含量足以维持组合物的pH在约3-7范围内的缓冲剂；和
(d) 少于2％重量的水。
发明详述
本发明涉及在激素组合物和活性方面表现储藏稳定性的甲状旁腺激素溶液。
作为活性成分，组合物或溶液可以加入全长，84个氨基酸形式的甲状旁腺激素，特别是属于人类的形式，hPTH(1-84)(SEQ ID NO：1)，可以来自利用肽合成技术重组的，或者来自人体液中提取的。参见，例如，美国专利5208041，引入本文作为参考。Kimura等(生物化学和生物物理学研究通讯(Biochem.Biophys.Res.Comm.)114(2)：493)报道了hPTH(1-84)的氨基酸序列(SEQ ID NO：1)。
组合物或溶液还可以加入作为活性成分的人PTH片段或其变体，或按照Kimmel等(内分泌学，1993，32(4)：1577)的报道经骨质疏松症卵巢切除大鼠模型证明具有人PTH活性的大鼠、猪或牛的PTH。
甲状旁腺激素片段最好加入至少前34个N-末端残基，例如PTH(1-34)(SEQ ID NO；2)、PTH(1-37)、PTH(1-38)和PTH(1-41)。或者，PTH的变体形式加入改善PTH稳定性和半衰期的1-5个氨基酸取代基，例如在8和/或18位用亮氨酸或其它改善PTH抗氧化稳定性的疏水氨基酸取代蛋氨酸残基，和在25-27区用胰蛋白酶惰性氨基酸(例如组氨酸或其它改善PTH抗蛋白酶稳定性的氨基酸)取代氨基酸。这些形式的PTH都包括在本文一般使用的术语“甲状旁腺激素”中。优选的激素是也公知为特立帕肽的人PTH(1-34)(SEQ ID NO：2)。该激素可以通过已知的重组或合成方法得到，例如美国专利4086196(引入本文作为参考)所述。
加到溶液或组合物中的稳定剂包括多羟基化合物，包括糖，优选单糖或二糖，例如葡萄糖、海藻糖、棉子糖、或蔗糖；糖醇例如，甘露醇、山梨醇或肌醇，以及多元醇例如甘油或丙二醇或它们的混合物。优选的多羟基化合物是甘露醇或丙二醇。多羟基化合物的浓度可以在约占总溶液的1到20 wt％范围内，优选约3到10 wt％。
本发明的溶液或组合物中应用的缓冲剂可以是任何药物可接受的并能够维持水溶液pH在3-7，优选3-6范围内的酸或盐的组合。有用的缓冲系统为，例如，乙酸盐、酒石酸盐或柠檬酸盐源。优选的缓冲体系是乙酸盐或酒石酸盐源，最优选的是乙酸盐源。缓冲液的浓度可以在约2mM到约500mM范围内，优选约2mM到100mM。
本发明的稳定的溶液或组合物还可以包括非肠道可接受的防腐剂。该防腐剂包括，例如，甲酚、苯甲醇、苯酚、苄基二甲基氯化铵、苄基二乙基氯化铵(benzethonium chloride)、氯丁醇、苯乙醇、羟苯甲酸甲酯、羟苯甲酸丙酯、硫汞撒和硝酸苯汞和乙酸苯汞。优选的防腐剂是m-甲酚(间-甲酚)或苯甲醇；更优选的是m-甲酚。应用的防腐剂的量可以占总溶液的约0.1到约2 wt％范围内，优选约0.3到约1.0 wt％。
因此，本发明提供了，例如，一种含有甘露醇、乙酸盐和m-甲酚的稳定的特立帕肽溶液，其在5℃时预期半衰期超过15个月。
本发明的甲状旁腺激素组合物可以，如果需要，以含不超过2％重量的水的粉末形式提供，其由无菌的激素水溶液冷冻干燥制备，所述水溶液通过混合如上所述的选择出来的甲状旁腺激素、缓冲剂和稳定剂制备。如果制备冻干粉末，尤其有用的缓冲剂是酒石酸盐源。尤其有用的稳定剂包括甘氨酸、甘露醇、蔗糖、海藻糖、棉子糖或其混合物。
本发明的PTH溶液和组合物加入医学有效量的PTH，医学有效量是参考治疗或医学诊断中所用的量而使用。加入本制剂中的甲状旁腺激素的特定量可以根据选择的PTH的类型和该制剂的预期最终应用预先确定。在一项应用中，本制剂用于治疗目的，特别是用于治疗骨质疏松症。骨质疏松症治疗需要经注射、理想的是经皮下注射给药重构制剂，给药的单位剂量反映规定的治疗方案，但，例如，对于人PTH(1-34)(SEQ ID NO：2)，为每位患者25-1000μg PTH/ml注射液，理想的注射体积为0.02-1.3mL。因此，理想的是，将纯化的PTH与缓冲剂和赋形剂相结合，形成含浓度范围为25-1000μg/ml，优选100-500μg/ml PTH的水溶液，然后对其进行无菌过滤，然后装入小瓶或药筒待用。
得到含所需量和浓度的缓冲剂、赋形剂和PTH的水溶液后，将各小瓶中装入所述溶液至所需体积。本发明的优点在于上述溶液可以用无菌水制备，不需要进行冷冻干燥处理。
在本发明的替代实施方案中，提供了重构到约1mL(0.8-1.2 mL)重构介质中时，形成100-500μg人PTH(1-34)(SEQ ID NO：2)的单位容器形式的制剂，因此将约1mL PTH水溶液制剂装入小瓶，用于随后的冷冻干燥。
在本发明的优选替换实施方案中，在重构于无菌水寸，经受冷冻干燥的PTH制剂包括25-1000μg/ml的人PTH(1-34)(SEQ ID NO：2)，2-8％重量的甘露醇，和含量能够缓冲所述制剂使其pH在3.0-6.5范围内的酒石酸盐源。在本发明的具体实施方案中，加入的酒石酸盐缓冲剂的量足以使pH缓冲在3.5-5.5。
除了其治疗用途外，可以配制并给药本发明的PTH组合物以辅助医学诊断，特别是协助诊断低血钙患者的甲状旁腺机能减退和假甲状旁腺机能减退。除了PTH的剂量，PTH制剂的组成将保持与本文所述的用于治疗用图的相同。静脉输注的、单剂量的等于200国际单位PTH活性的人PTH(1-34)(SEQ ID NO：2)制剂适用于该诊断目的。然后通过确定给药的PTH的效果或尿cAMP水平来进行诊断，其中cAMP升高表明甲状旁腺功能减退病症，而不是其假形。
下列实施例用于说明本发明，而不是用于对其进行限制。
实施例
实施例1
将0.1mg rhPTH(1-34)(SEQ ID NO：2)，50mg甘露醇，2.5mg m-甲酚，O.52mg乙酸和O.12mg乙酸钠混合到1ml蒸馏水中。
实施例2
将0.25mg rhPTH(1-34)(SEQ ID NO：2)，45．4mg甘露醇，3mg m-甲酚，0．41mg乙酸和0.1mg乙酸钠混合到1ml蒸馏水中。
将本发明实施例1和2的制剂与不含稳定剂，作为主要稳定剂的0.9％NaCl，20mM乙酸盐和10mM乙酸盐的溶液进行比较。通过确定一段时间后保留的rhPTH(1-34)(SEQ ID NO：2)量的百分比，测定稳定性。用HPLC进行测定。结果如表1和2所示。
表1 在50℃时主要稳定剂对rhPTH(1-34)的化学稳定性的影响
表2在30℃时rhPTH(1-34)的稳定性比较
实施例3
| 水 | 0.9％NaCl | 20 mM乙酸盐 | 10 mM乙酸盐 | |
| 时间，天 | 保留百分率(％) | |||
| 起始 | 100 | 100 | 100 | 100 |
| 7 | 74 | 81 | 84 | 80 |
| 14 | 55 | 58 | 67 | 71 |
| 20 mM乙酸盐 | 10 mM乙酸盐 | 实施例1 | 实施例2 | |
| 时间，天 | 保留百分率(％) | |||
| 起始 | 100 | 100 | 100 | 100 |
| 7 | 96 | 94 | 100 | - |
| 14 | 94 | 92 | 96 | 100 |
| 21 | 90 | 93 | 97 | - |
| 30 | - | 81 | 96 | 96 |
进行下列试验，以表明由本发明的稳定溶液制备的冻干粉末制剂比只用PTH(1-34)和甘露醇制备的对照物更稳定。
对照溶液和样品A到O溶液如前面所述进行制备，其成分和含量如表3所示。然后冷冻干燥溶液，将得到的冻干粉末制剂于40℃储存一个月。然后，利用HPLC测定各样品中保留的PTH(1-34)的含量。结果如表3所示。
表3 PTH(1-34)冻干制剂在40℃下放置一个月的稳定性
*2个月时稳定性为96％。
| 样品 | PTH(1-34)mg/mL | 填充剂 | 填充剂浓度mg/mL | 缓冲剂 | 缓冲剂浓度mM | PTH保留百分率(％) |
| 对照 | 0.2 | 甘露醇 | 40 | - | - | 78 |
| A | 0.5 | 甘露醇 | 30 | 乙酸盐 | 5 | 90 |
| B | O.5 | 甘氨酸 | 30 | 乙酸盐 | 5 | 98 |
| C | 0.5 | 蔗糖 | 30 | 乙酸盐 | 5 | 98 |
| D | 0.5 | 海藻糖 | 30 | 乙酸盐 | 5 | 97 |
| E | 0.5 | 棉子糖 | 30 | 乙酸盐 | 5 | 99 |
| F | 0.75 | 甘露醇 | 30 | 酒石酸盐 | 15 | 95 |
| G | 1.5 | 蔗糖和甘露醇 | 5/25 | 酒石酸盐 | 5 | 99 |
| H | 0.75 | 蔗糖和甘露醇 | 5/25 | 酒石酸盐 | 15 | 99 |
| I | 1.5 | 甘露醇 | 30 | 酒石酸盐 | 5 | 96 |
| J | 1.5 | 蔗糖 | 30 | 酒石酸盐 | 15 | 100 |
| K | 1.5 | 甘露醇 | 30 | 酒石酸盐 | 15 | 99 |
| L | 0.75 | 蔗糖 | 30 | 酒石酸盐 | 15 | 100 |
| M | 0.75 | 蔗糖 | 30 | 酒石酸 | 5 | 100 |
| 盐 | ||||||
| N | 1.5 | 蔗糖和甘露醇 | 5/25 | 酒石酸盐 | 15 | 99 |
| O | 1.5 | 蔗糖和甘露醇 | 5/25 | 乙酸盐 | 5 | 91* |
序列表〈110〉Eli Lilly和公司〈120〉稳定的特立帕肽溶液〈130〉3797.16WO01〈140〉新申请〈141〉1998-12-08〈150〉60/069，075〈151〉1997-12-09〈160〉2〈170〉Patentln Ver.2.0〈210〉1〈211〉84〈212〉PRT〈213〉人类〈400〉1Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn1 5 10 15Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser
35 40 45Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu
50 55 60Lys Ser Leu Gly Glu Ala Asp Lys Ala Asn Val Asp Val Leu Thr Lys65 70 75 80Ala Lys Ser Gln〈210〉2〈211〉34〈212〉PRT〈213〉人类〈400〉2Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn1 5 10 15Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30Asn Phe
Claims (25)
1．一种甲状旁腺激素溶液，包括：
(a)治疗有效量的甲状旁腺激素；
(b)有效量的稳定剂；
(c)含量足以维持组合物的pH在约3-7范围内的缓冲剂；和
(d)余量的水。
2．权利要求1的溶液，其中激素是选自PTH(1-34)、PTH(1-37)、PTH(1-38)、和PTH(1-41)的片段激素。
3．权利要求1的溶液，其中激素是人PTH(1-34)(SEQ ID NO：2)。
4．权利要求1的溶液，其中激素是人PTH(1-84)(SEQ ID NO：1)。
5．权利要求1的溶液，其中稳定剂是多羟基化合物。
6．权利要求5的溶液，其中多羟基化合物是甘露醇。
7．权利要求5的溶液，其中多羟基化合物是丙二醇。
8．权利要求1的溶液，其中缓冲剂是乙酸盐或酒石酸盐源。
9．权利要求8的溶液，其中缓冲剂是乙酸盐。
10．权利要求1的溶液，其进一步包括非肠道可接受的防腐剂。
11．权利要求10的溶液，其中防腐剂为m-甲酚或苯甲醇。
12．权利要求11的溶液，其中防腐剂为m-甲酚。
13．按照权利要求1的组合物，其为含有小于2％重量水的冷冻干燥的粉末形式。
14．一种甲状旁腺激素溶液，包括：(a) 治疗有效量的甲状旁腺激素；(b) 约1-20％重量的稳定剂；(c) 含量足以维持组合物的pH在约3-7范围内的缓冲剂，其选自乙酸盐或酒石酸盐源；(d) 约0.1-2％重量的非肠道可接受的防腐剂；和(e) 余量的水。
15．权利要求14的溶液，其中激素是PTH(1-84)。
16．权利要求14的溶液，其中激素选自PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)。
17．权利要求16的溶液，其中激素为人PTH(1-34)(SEQ ID NO：2)。
18．权利要求14的溶液，其中稳定剂为含量约为3-10％重量的多羟基化合物。
19．权利要求14的溶液，其中防腐剂是含量约为0.3-1.0％重量的m-甲酚或苯甲醇。
20．一种冷冻干燥粉末形式的药物组合物，包括：
(a)治疗有效量的甲状旁腺激素片段，选自PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)；
(b)有效量的稳定剂；
(c)含量足以维持组合物的pH在约3-7范围内的缓冲剂；和
(d)少于2％重量的水。
21．权利要求20的组合物，其中激素是人PTH(1-34)(SEQ ID NO：2)。
22．权利要求20的组合物，其中稳定剂选自甘氨酸、甘露醇、蔗糖、海藻糖、棉子糖和其混合物。
23．权利要求20的组合物，其中缓冲剂是乙酸盐或酒石酸盐源。
24．权利要求23的组合物，其中缓冲剂是酒石酸盐源。
25．权利要求20的组合物，其中稳定剂含量约为1-20％重量。
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