CN1105577C - 用于增加骨质量的甲状旁腺素和拉洛西芬 - Google Patents
用于增加骨质量的甲状旁腺素和拉洛西芬 Download PDFInfo
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
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Abstract
本发明包括通过给予PTH和拉洛两芬增加受治疗者骨质量的方法。本发明的另一个方面是通过给予PTH和拉洛西芬治疗受治疗者骨损失的方法。本发明还提供用于增加受治疗者骨质量的PTH和拉洛西芬的组合物。本发明的另一方面是用于治疗受治疗者骨损失的PTH和拉洛西芬的组合物。
Description
本发明涉及甲状旁腺素(PTH)与拉洛西芬(raloxifene)一同使用时在增加骨质量方面的用途。这种联合治疗可以使成骨速度增高而且质量增加。
Adams等人在美国专利5118667号上公开了采用骨生长因子与骨吸收抑制剂合用—或者同时在一个组合物中,或者依次使用—促进骨形成。
Slovik等人(J.Bone&Min.Res.1:377-381,1986)报道了用甲状旁腺素刺激骨生长。
本发明是通过给予拉洛西芬和PTH在活体上提供增加骨质量的联合疗法。这种联合治疗比单独使用所述成分能更有效地予防骨损失和软骨成骨。
本发明包括通过给予PTH和拉洛西芬增加受治疗者骨质量的方法。
本发明的另一方面是通过给予PTH和拉洛西芬治疗受治疗者骨损失的方法。
本发明还提供用于增加受治疗者骨质量的PTH和拉洛西芬的组合物。
本发明的另一方面是用于治疗受治疗者骨损失的PTH和拉洛西芬的组合物。
当说及拉洛西芬时,应当理解为包括其盐和溶剂化物。所说的PTH不仅包括完全的人激素,而且包括能促进骨生长的部分激素如PTH1-34和类似物,所述类似物中氨基酸序列略有改变,但仍保留有骨生长促进性能,例如PTH-RP。
术语“抑制骨吸收”是指通过直接或间接改变破骨细胞的形成或代谢预防骨损失。尤其是抑制现有骨由矿物相和/或有机基质相移开。因此,本文中所用的术语“骨吸收抑制剂”是指通过直接或间接改变破骨细胞的形成或代谢防止骨损失的药剂。
术语“成骨有效的”是指引起骨形成和分化的量。如本文所用的成骨有效剂量也是“药理上有效的”。
本文所用“受治疗者”一词是指需要治疗,即需要骨修复或软骨成骨的活脊椎动物。例如哺乳动物或鸟。这样的需要在骨折、骨不连合、缺损、假体植入等情况下局部出现。这样的需要也在全身性骨疾病如在下述情况下出现:骨质疏松、骨关节炎、佩吉特氏病、骨软化、骨钙质缺乏、多发性骨髓瘤和其它形式的癌症,以及老年性骨质量损失。
用在本文中的“治疗”一词是指:(1)给予受治疗者足够量能产生予防性作用的物质,以防止衰弱和/或不健康状况发展;或(2)给予受治疗者足够量的物质以减轻或消除疾病和/或疾病症状,以及衰弱和/和不健康状况。
拉洛西芬可按已确立的方法例如在美国专利4418068号中详述的方法来制备,PTH可按已确立的方法合成或重组制备。PTH 1-34可从Bachem(Torrence,加利福尼亚)购买。
预防骨损失和/或补偿已损失的骨和/或增加骨质量的药物可以用切除卵巢的大鼠来评价。该动物模型在本领域已完全确立(参见例如Wronski,等人(1985)Calcif.Tissue Int 37:324-328;Kimmel,等人(1990)Calcif Tissue Int 46:101-110;和Durbridge,等人(1990)Calcif.因而这些文献被全部引用)。Wronski,等人((1985)Calcif.Tissue Int.43:179-183))描述了在切除卵巢的大鼠中骨损失和骨更新的关系。Hock等人也描述了未成熟大鼠的该用途((1988)Endocrinology,122卷,2899-2904页)。
PTH和拉洛西芬可以给受治疗者依次使用、同时使用或以单一组合物的形式同时使用。若依次给药,给予PTH和拉洛西芬之间的时间间隔一般应为一周至一年,最好是一周至六个月。在优选的给药方案中,受治疗者在使用PTH(用或未用拉洛西芬)后,应在停用PTH后使用拉洛西芬。
包括PTH和/或拉洛西芬的给药用本发明的药用制剂一般包括成骨有效量促进骨生长的骨生长因子,和药学上可接受的赋形剂。适宜的赋形剂包括可用于肠胃外给药的大多数载体,包括水、盐水、林格氏溶液、Hank氏溶液和葡萄糖溶液、右旋乳糖(lactose dextrose)溶液、乙醇溶液、甘油溶液、白蛋白溶液等。这些组合物可以任选地包括稳定剂、抗氧剂、抗菌剂、防腐剂、缓冲剂、表面活性剂及其它辅助添加剂。PTH和/或拉洛西芬也可以离子电渗片(iontophoretcipatch)形式给药、对适宜肠胃外给药的赋形剂的全面讨论可以见E.W.Martin的“Remington′s Pharmaceutical Sciences”(Mack Pub.Co.,本期涉及赋形剂媒体和配制的章节作为参考被结合在本文中)。这样的制剂一般对于本领域技术人员是已知的并被系统使用以提供系统治疗。
若所述联合是以单一组合物形式给药时,PTH与拉洛西芬的摩尔比应为约10∶1-1∶10,优选5∶1-1∶5,1∶1最佳。此外,若以单一组合物形式给药,它们可以是该组合物的单独组分,或者它们可以互相结合。
所需准确剂量应随受治疗者的年龄、身材、性别和状态、待治疗疾病的性质及严重程度等变动,因此预先不能确定准确的有效量,应由保健医(caregiver)确定。但是适当的量可以通过用动物模型进行的常规实验来确定。一般来讲,用于系统治疗的PTH的有效量每天应在约0.001μg/kg体重至10mg/kg体重的范围内。拉洛西芬的有效剂量每天在0.001-10mg/kg体重范围内。
本发明方法和组合物可用于治疗骨折、缺损和导致骨衰弱的疾病例如骨质疏松、骨关节炎,佩吉特氏病、骨钙质缺乏、骨软化、由多发性骨髓瘤和其它形式的癌症引起的骨损失、由其它医疗(例如类固醇类)的副作用引起的骨损失和老年性骨质量损失。
按照一种使用方法,PTH和拉洛西芬可系统性口服和/或肠胃外使用,包括皮下或静脉注射,和/或鼻内给药。
按照另一种使用方法,可将PTH局部给至需要骨生长或修复的特定部位,在该部位同时给予拉洛西芬,或者在单独的赋形剂中给予拉洛西芬,或者局部给与拉洛西芬,并在单独的赋形剂中给予PTH。因此,可以通过注射或手术植入,将PTH或/或拉洛西芬直接植入至待治疗部位。适宜的载体包括水凝胶、控释或缓释装置(例如Alzet微型泵)、聚乳酸格胶原基质、目前优选的载体是含有微粒磷酸钙矿物成分的不全肽(atelopeptide)胶原,例如同种或异种移植原纤维不全肽胶原(homologous or xenographic fibrillar atelopeptidecollagen)(例如Zyderm胶原植入片,可购自Collagen Corpora-tion,Palo Alto,加利福尼亚)与羟磷灰石磷酸三钙(HA-TCP,可购自Zimmer,Inc.,Warsaw,In.)的组合物。
牙植入物和矫形植入物可用PTH和拉洛西芬的混合物包衣以增强该植入物与骨的接触。或者,可用PTH对该植入物包衣,并同时或其后给予单独的赋形剂中的拉洛西芬、反之亦然。
一般来讲,植入物可以按下述过程用PTH和/或拉洛西芬包衣。将PTH(和拉洛西芬,若有必要的话)按0.01μg/ml至200mg/ml范围内的浓度溶于含2mg/ml血清白蛋白的磷酸盐缓冲的盐水(PBS)中。将植入物的有孔端浸入该溶液中,并凉干(或冻干)或立即植入骨部位。若有必要,可以通过加入透明质酸盐(hyaluronate)(终浓度为0.1-100mg/ml)或其它药学上可接受的赋形剂来增加包衣溶液的粘度,或者,将含PTH(和拉洛西芬,若有必要的话)与胶原凝胶或人胶原(例如Zydorm胶原植入片,Collagen Corp.,Palo Alto,加利福尼亚)混合成2-100mg/ml的胶原浓度,以形成糊状物或凝胶,然后将其用于对植入物的有孔端进行包衣。将该包衣后的植入物立即置于骨部位或将其凉干,并在植入前将其用PBS再水合,目的是最大限度地使新骨形成进入植入物中,而最低限度地使软组织的向内生长进入植入物部位。
实施例
下列实施例用来向本领域普通技术人员完全公开并说明如何使用本发明的组合物和方法,对本发明者认定的本发明范围并无限制。
大鼠是切除卵巢的(OVX)4周龄鼠,按8μg/100g/天单独皮下(SC)给予赋形剂(V)或hPTH 1-34(P),或者与皮下给予0.3mg/100g/天拉洛西芬(R)合用如下:V24天;R24天;P和R24天;P12天然后V12天;P12天然后R12天;V12天然后R12天。将大鼠在第24天处死,并收集血液、股骨、腰椎和肾。骨质量按远侧半侧股骨(distalhalf femurs)的Ca和干重(DW)来测定;脊椎被处理供组织形态测量学研究。
由于给予拉洛西芬的OVX大鼠的终体重小OVX鼠或完整鼠的体重,因此数据被校正成每100g体重的值。OVX鼠的远侧半侧股骨的Ca和干重与对照(sham)鼠比较,降低15%。骨质量由拉洛西芬(R24天)增加约25%,由PTH(24天)增加约42%。停药后(P12天V12天),PTH的同化作用丧失。拉洛西芬在与PTH同时使用时具有加和效果(与OVX对照相比增加65%)。在所有组之间比较股骨长度、血清Ca和肾Ca,
最终体重
股骨长度对照-赋形剂 (12d) 赋形剂 (12d) 201±4 28.6±0.4OVX-赋形剂 (12d) 赋形剂 (12d) 241±5a 28.8±0.3OVX-PTH (12d) PTH (12d) 241±4ac 29.8±0.2OVX-拉洛西芬 (12d) 拉洛西芬 (12d) 189±5b 28.5±0.2OVX-PTH和拉洛西芬 (12d) PTH和拉洛西芬 (12d) 190±4b 28.8±0.2OVX PTH (12d) 赋形剂 (12d) 245±4a 29.6±0.3OVX PTH (12d) 拉洛西芬 (12d) 208±2bc 30.0±1.2OVX 拉洛西芬 (12d) 赋形剂 (12d) 208±6bc 29.0±0.3对于8只鼠的组,数据以平均值±sem表示。显著性差异:,p<0.05,a对对照-赋形剂(sham-vehicle)c对OVX拉洛西芬(12+12d)
将大鼠在4周龄时切除卵巢,约10周时处死,增重大于同龄的完整鼠。PTH不改变该增重。拉洛西芬在有或无PTH存在时阻止与OVX有关的增重。给拉洛芬12天然后再给12天赋形剂的大鼠的增重比OVX对照的少,但比继续给拉洛西芬的多。
因对股骨长度影响,测定纵骨生长的意义在于:体重改变并不表明骨生长改变(大鼠刚好变得更瘦)。
远侧股骨的骨质量干重
总骨 总骨 总骨
1-12
13-24
DW/100g BW
Ca
DW1.对照 V V 18.5±0.5ab 9.0±0.4ab 37.1±0.8ab2.OVX V V 15.8±0.5abcd 9.3±0.5ab 38.4±1.4ab3.OVX R R 19.7±0.5ab 9.6±0.4ab 37.1±1.2ab4.OVX P P 22.4±0.4b 12.2±0.4 54.2±1.75.OVX P&R P&R 26.1±0.9a 11.6±0.4 49.5±2.06.OVX P V 16.7±0.3abc 9.9±0.3ab 41.0±1.0ab7.OVX P R 17.8±0.4abcd 10.0±0.7ab 37.1±1.0ab8.OVX V R 16.8±0.4abc 9.0±0.5ab 34.9±1.0abP<0.05,a对PTH;b对PTHOR;c对ralox;d对OVXV=赋形剂R=拉洛西芬P=PTH
Ca
DW=远侧股骨的总骨质量
%均值间的增加1. -3% -3%2.3. 3% 0%4. 31% 41%5. 25% 29%6. 6% 7%7. 7% -3%8. -3% -1%总骨 =骨皮质和小梁骨之和
远侧股骨的骨质量
小梁骨
骨皮质
Ca DW DW对照 5.2±0.2 9.7±0.3 27.4±0.6V 4.7±0.3 8.5±0.5 29.9±1.0P 9.3±0.5a 16.5±0.8 37.7±1.5aR 5.6±0.4 9.7±0.5 27.5±0.9P&R 7.6±0.6b 13.4±1.06 36.1±1.46P-V 5.6±0.1 10.8±0.4 30.2±1.2P-R 5.2±0.3 9.1±0.6 28.0±0.7R-V 4.3±1.0 8.6±0.5 26.3±1.1
P<0.05,a,b对所有其它组。表明小梁骨和骨皮质的增加相同。
因此,用PTH处理切除卵巢的大鼠导致骨形成增加,但该增加被同时用拉洛西芬处理显著加大。
Claims (6)
1.一种药用制剂,它包括甲状旁腺素和拉洛西芬,和一种或多种药学上可接受的载体。
2.权利要求1的制剂,其中甲状旁腺素与拉洛西芬的摩尔比是10∶1-1∶10。
5.权利要求2的制剂,其中所述制剂被用来增加骨质量或治疗骨损失。
4.甲状旁腺素和拉洛西芬合用用于制备增加人的骨质量或治疗人的骨损失的药物的用途。
5.权利要求4的用途,其中甲状旁腺素和拉洛西芬被同时使用。
6.权利要求4的用途,其中甲状旁腺素和拉洛西芬被依次使用。
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