CN1543357A - 作为甲状旁腺激素片段的口服递送剂的5-cnac - Google Patents
作为甲状旁腺激素片段的口服递送剂的5-cnac Download PDFInfo
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- CN1543357A CN1543357A CNA028160843A CN02816084A CN1543357A CN 1543357 A CN1543357 A CN 1543357A CN A028160843 A CNA028160843 A CN A028160843A CN 02816084 A CN02816084 A CN 02816084A CN 1543357 A CN1543357 A CN 1543357A
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- disodium salt
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
本发明提供了用于有效口服递送甲状旁腺激素PTH的药物组合物，以及施用所述组合物的方法。此外，还提供了刺激新骨形成和治疗和/或预防骨质疏松症的方法。
Description
发明背景
1.发明领域
本发明涉及甲状旁腺激素(PTH)的口服递送(delivery)。哺乳动物例如人、牛、猪的甲状旁腺激素，即hPTH、bPTH、pPTH，为84个氨基酸残基组成的单股多肽链，其分子量约为9500。具体而言，本发明涉及包括至少头28个N-末端氨基酸残基(PTH(1-28))、不超过并包括头41个N-末端氨基酸残基(PTH(1-41)的PTH片段。更具体地而言，本发明涉及用于口服施用PTH的药物组合物，所述组合物包含PTH(1-28)至(1-41)和N-(5-氯水杨酰基)-8-氨基辛酸(5-CNAC)。
2.相关技术描述
在动物和人类中用PTH、PTH相关肽和PTH类似物进行的PTH研究已证实其在增加骨形成和骨重吸收方面的有效性，并且已经激起了对其用于治疗骨质疏松症及相关骨病变的兴趣。然而，已证实在哺乳动物中口服施用PTH是困难的，这至少部分是由于PTH在胃肠道中没有足够的稳定性以及PTH不易于通过肠壁被输送至血流中。
美国专利5,773,647号(’647号专利)描述了193种可用于施用活性剂、包括PTH的载体化合物。其中特别述及的一种载体化合物为N-(5-氯水杨酰)-8-氨基辛酸(5-CNAC)，其通式为
‘647号专利第6栏中的实施例2描述了11种不同的给药(dosing)组合物的制备，有些经结肠内(IC)、有些经口管饲(PO)施用，每种组合物均含有甲状旁腺激素和载体，且各组合物中的载体不同。一种IC给药组合物是使用5-CNAC作为载体而制备。其中的实施例3描述了使用实施例2制备的给药溶液对雄性Sprague-Dawley大鼠进行给药的体内实验。收集血样并对每只大鼠的血浆PTH浓度进行定量。
令人惊讶的是，现已发现：相对于其它PTH及其它载体而言，5-CNAC与特别的PTH片段，即包括至少头28个N-末端氨基酸残基(PTH(1-28))且包括并不超过头41个N-末端氨基酸残基(PTH(1-41))的PTH片段的组合，当口服施用时获得了意想不到的高PTH血浆浓度，并且迅速达到Cmax，使其具有骨形成作用。
发明概述
因此，本发明涉及适用于口服施用PTH片段的药物组合物和施用这种组合物的方法。
具体而言，本发明涉及口服施用的药物组合物，其包含治疗有效量的PTH片段和5-CNAC，所述PTH片段选自PTH(1-28)至PTH(1-41)。优选地，PTH为人甲状旁腺激素，即hPTH。
在另一个实施方案中，本发明涉及口服施用有效剂量的PTH的方法，其包括向需要PTH的患者口服施用包含治疗有效量的PTH片段和5-CNAC的药物组合物，所述PTH片段选自PTH(1-28)至PTH(1-41)。
本发明还涉及刺激新骨形成的方法，其包括向需要新骨形成的患者口服施用包含治疗有效量的PTH片段和5-CNAC的药物组合物，所述PTH片段选自PTH(1-28)至PTH(1-41)。
在进一步的实施方案中，本发明涉及治疗或预防骨质疏松症的方法，其包括向需要所述治疗或预防的患者口服施用包含治疗有效量的PTH片段和5-CNAC的药物组合物，所述PTH片段选自PTH(1-28)至PTH(1-41)。
在更进一步的实施方案中，本发明涉及5-CNAC在制备适合于口服施用选自PTH(1-28)至PTH(1-41)的PTH片段的药物组合物中的用途。
本发明的其它特点和优势将在以下本发明的详细描述中体现。
发明详述
所述PTH片段可以是任何甲状旁腺激素的片段，尤其是哺乳动物例如人、牛和猪的甲状旁腺激素，即hPTH、bPTH和pPTH，且尤其是hPTH的片段，并且可包括至少头28个N-末端氨基酸残基(PTH(1-28))、不超过且包括头41个N-末端氨基酸残基(PTH(1-41))，并且对包括PTH(1-28)、PTH(1-31)、PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)没有限制。特别优选人甲状旁腺激素(1-34)。这些甲状旁腺激素片段均市售可得或可通过重组或肽合成获得。
当用于本发明时，5-CNAC，即N-(5-氯水杨酰基)-8-氨基辛酸，可以是游离酸、其类似物、其单钠和二钠盐、钠盐的乙醇溶剂化物和钠盐的单水合物及其任意组合。尤其有用的是5-CNAC的游离酸、二钠盐及其单水合物。N-(5-氯水杨酰基)-8-氨基辛酸已在前述’647号专利中述及并且可通过其中所述的方法制备，所述专利的内容在此引入作为参考。其钠盐及醇溶剂化物和水合物以及制备它们的方法均在WO 00/059863中述及。
二钠盐可以由乙醇溶剂化物制备，通过本领域已知的方法使乙醇溶剂化物蒸发或干燥而形成无水二钠盐。干燥通常在约80℃至约120℃的温度下进行，优选约85℃至约90℃且最优选约85℃。干燥步骤通常在26”Hg或更高的压力下进行。基于无水二钠盐的100％总重量，无水二钠盐通常含有以重量计低于约5％、且优选以重量计低于约2％的乙醇。
N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐也可通过用水制成N-(5-氯水杨酰基)-8-氨基辛酸浆液并且加入两摩尔当量的氢氧化钠、醇钠等水溶液而制备。适宜的醇钠包括但不限于甲醇钠、乙醇钠及其组合。
制备二钠盐的另一种方法是使N-(5-氯水杨酰基)-8-氨基辛酸与1摩尔当量的氢氧化钠反应形成单钠盐、随后再加入1摩尔当量的氢氧化钠以生成二钠盐。
通过真空蒸馏将含有二钠盐的溶液浓缩为稠浆，可以固体形式分离二钠盐。此稠浆可于真空炉中干燥以获得固体形式的N-(5-氯水杨酰基)-8-氨基辛酸二钠盐。所述固体还可通过对二钠盐的水溶液进行喷雾干燥而分离。
前述WO 00/059863中述及的乙醇溶剂化物包括但不限于乙醇溶剂的分子或离子与N-(5-氯水杨酰基)-8-氨基辛酸二钠盐的分子或离子的分子或离子复合物。通常，对于每分子N-(5-氯水杨酰基)-8-氨基辛酸二钠盐，乙醇溶剂化物含有约一个乙醇分子或离子。
N-(5-氯水杨酰基)-8-氨基辛酸二钠盐的乙醇溶剂化物可通过将N-(5-氯水杨酰基)-8-氨基辛酸溶解于乙醇而制备。通常，将每克N-(5-氯水杨酰基)-8-氨基辛酸溶于约1至约50ml乙醇中，且通常约2至约10ml乙醇中。然后使N-(5-氯水杨酰基)-8-氨基辛酸/乙醇溶液与相对于N-(5-氯水杨酰基)-8-氨基辛酸摩尔过量的含钠盐如含单钠的盐进行反应，生成乙醇溶剂化物，即对于每摩尔N-(5-氯水杨酰基)-8-氨基辛酸存在超过1摩尔的钠阳离子。适宜的单钠盐包括但不限于氢氧化钠；醇钠如甲醇钠和乙醇钠；以及前述的任何组合。优选地，将至少约2摩尔当量的单钠盐加至乙醇溶液中，即对于每摩尔N-(5-氯水杨酰基)-8-氨基辛酸存在至少约2摩尔的钠阳离子。通常，反应在低于或在混合物的回流温度如室温下进行。然后通过本领域已知的方法回收乙醇溶剂化物，如浓缩常压蒸馏所得的浆液、冷却浓缩的浆液并且过滤固体。然后可将回收的固体真空干燥，得到乙醇溶剂化物。
N-(5-氯水杨酰基)-8-氨基辛酸二钠盐的水合物可如上所述通过干燥乙醇溶剂化物以形成无水二钠盐且将无水二钠盐水合而制备。优选地，形成二钠盐的单水化物。由于无水二钠盐的吸湿性强，因此在暴露于空气湿度中可形成水合物。通常，水合步骤在约室温至约50℃、优选室温至约30℃的温度下、且环境相对湿度至少50％的条件下进行。或者，可以使用蒸汽对无水二钠盐进行水合。
待施用的PTH片段的量通常是有效刺激新骨形成的量，即治疗有效量。该量不可避免地随待治疗个体的年龄、体积(size)、性别和条件、待治疗疾病的性质和严重程度等而变化。然而，当预计多次施用组合物时，所施用的量可低于治疗有效量，即总有效量可以以累计剂量单位的形式施用。当组合物提供药理活性物质的持续释放时，PTH的量还可大于有效量。所使用PTH的总量可通过本领域技术人员已知的方法确定。然而，通常在日剂量约0.001μg/kg至约10mg/kg动物体重、优选1μg/kg至约6μg/kg体重时可在全身获得满意的结果。
本发明的药物组合物通常含有递送有效量的5-CNAC，即足以递送PTH以达到所需效果的量。通常，5-CNAC的含量以重量计为组合物总重量的2.5％至99.4％、更优选为25％至50％。
本发明药物组合物的口服施用可有规律地进行，例如每日或每周一次或多次；间断进行，例如在一天或一周内不规律施用；或循环施用，例如有规律地施用几天或几周后停止施用一段时期。
本发明药物组合物的剂型可以是任何已知的形式，例如液体或固体剂型。
液体剂型包括溶液乳剂、混悬剂、糖浆剂和酏剂。除PTH和5-CNAC外，液体制剂还可含有本领域常用的惰性赋形剂，如增溶剂例如乙醇；油如棉籽油、蓖麻油和芝麻油；润湿剂；乳化剂；助悬剂；甜味剂；矫味剂和溶剂如水。
固体剂型包括胶囊剂、软胶囊、片剂、囊片(caplet)、粉剂、颗粒剂或其它固体口服剂型，所有这些剂型可通过本领域已知的方法制备。
药物组合物可额外地包含通常所使用量的添加剂，包括但不限于pH调节剂、防腐剂、矫味剂、遮味剂、芳香剂、湿润剂、张力剂(tonicifier)、着色剂、表面活性剂、增塑剂、润滑剂如硬脂酸镁、助流剂、助压剂(compression aid)、增溶剂、赋形剂、稀释剂如微晶纤维素，例如由FMC公司提供的Avicel PH 102，或它们的任意组合。其它添加剂可包括磷酸盐缓冲剂、柠檬酸、二元醇和其它分散剂。
组合物还可包含一种或多种酶抑制剂，如放线酰胺素或表放线酰胺素(epiactinonin)及其衍生物，抑肽酶、抑肽酶(Trasylol)和Bowman-Birk抑制剂。
此外，转运抑制剂，即ρ-糖蛋白如Ketoprofin，也可存在于本发明的组合物中。
本发明的固体药物组合物可通过常规方法制备，例如通过将PTH片段、5-CNAC和任何其它成分的混合物混合、捏制并填充至胶囊中，或不填充至胶囊而进行模塑、然后进一步压片或压模以得到片剂。此外，通过已知的方法可制成固体分散体，随后进一步加工形成片剂或胶囊。
优选地，本发明药物组合物中的各成分被均匀或均一地混合于整个固体剂型中。
甲状旁腺激素适用于预防或治疗所有与钙缺失增加或重吸收有关的或需要刺激骨形成并将钙固定于骨中的骨疾病，如各种原因(如幼年、绝经期、绝经期后、创伤后、由高龄引起或由类皮质激素-类固醇治疗引起的、或废用性而导致)的骨质疏松症、骨折、骨病，包括骨脱矿的急性和慢性期、骨软化症、牙周骨缺失或由于关节炎或骨关节炎或肿瘤(如骨转移)引起的骨缺失，或用于治疗甲状旁腺功能减退症。
甲状旁腺激素尤其适用于预防或治疗各种原因的骨质疏松症。
根据本发明的另一个实施方案，PTH可用作其它治疗的添加剂或辅药，所述其它治疗例如(例如在骨质疏松症的治疗中的)使用骨重吸收抑制剂的治疗，尤其是使用以下药物的治疗：钙、降钙素或其类似物或衍生物，例如鲑鱼、鳗或人降钙素；类固醇激素，例如雌激素、部分雌激素激动剂或雌激素-孕激素组合；SERM(选择性雌激素受体调节剂)，例如雷诺昔芬(raloxifene)、lasofoxifene、TSE-424、FC1271，7-甲异炔诺酮(Tibolone，Livial)，维生素D或其类似物或PTH释放活化剂，或二膦酸盐类药物，例如氯膦酸(clodronic acid)、依替膦酸(etidronic acid)、帕米膦酸(pamidronic acid)、aledronic acid、依班膦酸(ibandronic acid)、唑来膦酸(zoledronic acid)、利塞膦酸(risedronic acid)或替鲁膦酸(tiludronic acid)及它们的盐和水合物。
当PTH例如作为骨重吸收抑制治疗的辅药被联合施用时，其用于联合施用抑制剂的剂量显然将随着所使用抑制剂药物的类型而变化，例如根据所治疗的病症使用的是类固醇还是降钙素，根据施用方案等使用的是治疗性还是预防性治疗。
本发明的口服施用可以在任何需要它的动物中进行，包括但不限于哺乳动物如啮齿类动物、牛、猪、狗、猫和灵长类动物，尤其是人类。
以下实施例进一步说明本发明。
实施例1
按下述方式制备了以下胶囊：
自800μg hPTH*制备的胶囊(胶囊1A)
自400mg 5-CNAC**/800μg hPTH*制备的胶囊(胶囊1B)
*PTH片段为可自Sigma购得的人甲状旁腺激素的片段1-34。
**5-CNAC为N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐。
仅含有hPTH的胶囊是通过称量400μghPTH并直接将其置于每个胶囊中而制备。hPTH/5-CNAC胶囊是通过称出各个成分、将它们混合在一起制成干燥的均匀混合物、随后手工将400mg混合物填充至每个胶囊中而制备。
实施例2
灵长类动物施用
将实施例1制备的胶囊按如下方式施用于恒河猴(Rhesus monkey)：4只猴为一组，按如下方法向每只猴施用1粒实施例1制备的胶囊：
恒河猴于给药前整晚禁食并且在研究期间被束缚于椅中，保持完全清醒。经强饲管口服施用所述胶囊后给予10ml水。
于施用后0、0.25、0.5、0.75、1、1.5、2、3、4、5和6小时收集血样。通过放射免疫测定法测定血浆hPTH浓度。将得自各组猴的灵长类血浆PTH结果平均并计算最大平均血浆浓度。单纯PTH组的结果报告于表1，hPTH/5-CNAC组的结果报告于表2。
表1
| 单纯hPTH | |||||||||||
| 向恒河猴口服施用后的血浆hPTH浓度(pg/ml) | |||||||||||
| 剂量：1粒胶囊1D | |||||||||||
| 动物 | 时间[小时] | ||||||||||
| 序号 | 0 | 0.25 | 0.50 | 0.75 | 1 | 1.5 | 2 | 3 | 4 | 5 | 6 |
| R927 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| S982 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 平均值 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 标准偏差(SD) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 标准误差(SEM) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| LLOQ＝25pg/ml，低于LLOQ的浓度设定为零。 | |||||||||||
表2
| hPTH/5-CNAC | |||||||||||
| 向恒河猴口服施用后的血浆hPTH浓度(pg/ml) | |||||||||||
| 剂量：1粒胶囊1B | |||||||||||
| 动物 | 时间[小时] | ||||||||||
| 序号 | 0 | 0.25 | 0.50 | 0.75 | 1 | 1.5 | 2 | 3 | 4 | 5 | 6 |
| R944 | 0 | 83 | 191 | 300 | 360 | 262 | 154 | 35 | 0 | 0 | 0 |
| S963 | 0 | 127 | 332 | 663 | 1258 | 150 | 34 | 0 | 0 | 0 | 0 |
| 平均值 | 0 | 105 | 262 | 482 | 809 | 206 | 94 | 17 | 0 | 0 | 0 |
| 标准偏差(SD) | 0 | 31 | 100 | 257 | 635 | 79 | 85 | 25 | 0 | 0 | 0 |
| 标准误差(SEM) | 0 | 22 | 71 | 182 | 449 | 56 | 60 | 17 | 0 | 0 | 0 |
如表1和表2中数据所示，5-CNAC显著促进hPTH片段的口服递送。此外，表2的数据显示：PTH血浆浓度迅速达到Cmax，可发挥骨形成作用。
前述实施方案和实施例仅仅对本发明进行说明而并非对其进行限制。许多其它实施方案和变体属于本发明的范围并且易于为本领域技术人员所理解。
Claims (21)
1.用于口服施用的药物组合物，其包含治疗有效量的PTH片段和5-CNAC，所述PTH片段选自PTH(1-28)至PTH(1-41)。
2.权利要求1的药物组合物，其中的PTH选自PTH(1-28)、PTH(1-31)、PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)。
3.权利要求1的药物组合物，其中的PTH为PTH(1-34)。
4.权利要求1的药物组合物，其中的PTH为重组PTH。
5.权利要求3的药物组合物，其中的PTH为重组PTH。
6.权利要求1的药物组合物，其中的PTH为人甲状旁腺激素。
7.权利要求6的药物组合物，其中的人甲状旁腺激素为hPTH(1-34)。
8.权利要求1的药物组合物，其中的5-CNAC选自N-(5-氯水杨酰基)-8-氨基辛酸的游离酸、二钠盐及其单水合物。
9.权利要求1的药物组合物，其中的5-CNAC为N-(5-氯水杨酰基)-8-氨基辛酸。
10.权利要求1的药物组合物，其中的5-CNAC为N-(5-氯水杨酰基)-8-氨基辛酸的二钠盐。
11.口服施用有效剂量的PTH的方法，其包括向需要PTH的患者口服施用包含治疗有效量的PTH片段和5-CNAC的药物组合物，所述PTH片段选自PTH(1-28)至PTH(1-41)。
12.权利要求11的方法，其中的PTH选自PTH(1-28)、PTH(1-31)、PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)。
13.权利要求11的方法，其中的PTH为hPTH(1-34)。
14.权利要求11的方法，其中的PTH为重组PTH。
15.权利要求11的方法，其中的PTH为重组hPTH。
16.权利要求11的方法，其中的5-CNAC选自N-(5-氯水杨酰基)-8-氨基辛酸的游离酸、二钠盐及其单水合物。
17.权利要求11的方法，其中的5-CNAC为N-(5-氯-水杨酰基)-8-氨基辛酸。
18.权利要求11的方法，其中的5-CNAC为N-(5-氯-水杨酰基)-8-氨基辛酸的二钠盐。
19.刺激新骨形成的方法，其包括向需要新骨形成的患者口服施用包含治疗有效量的PTH片段和5-CNAC的药物组合物，所述PTH片段选自PTH(1-28)至PTH(1-41)。
20.治疗或预防骨质疏松症的方法，其包括向需要所述治疗或预防的患者口服施用包含治疗有效量的PTH片段和5-CNAC的药物组合物，所述PTH片段选自PTH(1-28)至PTH(1-41)。
21.5-CNAC在制备适合于口服递送选自PTH(1-28)至PTH(1-41)的PTH片段的药物组合物中的用途。
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| AU2003234716A1 (en) * | 2002-04-10 | 2003-10-27 | Joel M. Linden | Use of a2a adenosine receptor agonists for the treatment of inflammatory diseases |
| US20050054557A1 (en) * | 2002-05-09 | 2005-03-10 | Goldberg Michael M. | Compositions for delivering parathyroid hormone and calcitonin |
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| WO2006076692A1 (en) * | 2005-01-12 | 2006-07-20 | Emisphere Technologies, Inc. | Compositions for buccal delivery of parathyroid hormone |
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| WO2007035718A2 (en) | 2005-09-19 | 2007-03-29 | Emisphere Technologies, Inc. | Crystalline forms of the di-sodium salt of n-(5-chlorosalicyloyl)-8-aminocaprylic acid |
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| AU2006315132A1 (en) * | 2005-11-10 | 2007-05-24 | Board Of Control Of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
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| EP2509996A1 (en) | 2009-12-07 | 2012-10-17 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| WO2012130193A1 (en) | 2011-03-31 | 2012-10-04 | Zentiva, K.S. | Non-covalent soluble complexes of teriparatide with polysaccharides and a dosage form of teriparatide for oral administration |
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| CN113694190A (zh) * | 2015-02-09 | 2021-11-26 | 安特拉贝欧有限公司 | 骨质疏松症的治疗 |
| CN113713090A (zh) * | 2015-02-09 | 2021-11-30 | 安特拉贝欧有限公司 | 骨质疏松症的治疗 |
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