CN1120314A - 治疗骨质疏松症的方法和组合物 - Google Patents
治疗骨质疏松症的方法和组合物 Download PDFInfo
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- CN1120314A CN1120314A CN94191682A CN94191682A CN1120314A CN 1120314 A CN1120314 A CN 1120314A CN 94191682 A CN94191682 A CN 94191682A CN 94191682 A CN94191682 A CN 94191682A CN 1120314 A CN1120314 A CN 1120314A
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- estrogen
- potassium salt
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- patient
- osteoporosis
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Abstract
用于治疗骨质疏松的下列活性成分的结合药物:(a)可药用的碱化钾盐,该盐能产生羟基离子,从而能降低组织液或尿液的酸性,且所述钾盐选自碳酸氢钾和羧酸的钾盐,所述羧酸的钾盐能转化成碳酸氢盐,从而在体内被碱化,以及(b)能有效治疗骨质疏松的***,其用量为低至其标准推荐剂量的1/10;所存在的碱化钾盐的量为使得结合药物比单独给用相同量所述***治疗骨质疏松时实质上更有效的量。
Description
本申请是1989年10月17日提出的申请号为420,597专利申请,1992年11月15日授权的美国专利5,171,583的接续,其中上述专利是1988年10月21日提出的申请号为260,856,现已放弃的专利申请书的接续。
本发明涉及一种新的治疗人类骨质疏松症的方法,更具体地讲,包括利用碱性钾盐和对此类治疗有效的***结合给药治疗骨质疏松症的方法和组合物,该结合给药能够降低通常***治疗骨质疏松所伴随的健康危险和副作用。
骨质疏松病是一种骨代谢疾病,其特征病理上表现为骨数量绝对减少,临床上表现为骨折敏感性增强。Riggs等,N,Engl.J.Med.(1986),314:1676;Rusbach等,Textbook ofEndocrinology,Ed(s)Williams,(1981),p.922;Riggs,Cecil Textbook of Medicine,Ed(s)Wyngaarden等,(1985),p.1456;Riggs等,Am.J.Med.,(1983),75:899。
已有几类生化标记一同被考虑用于诊断骨质疏松的病人,或者用于研究治疗骨质疏松的效力。例如,尿羟基脯氨酸***率被广泛用作骨吸收的标记。Klein等Metabolism 2,Vol.13,No.3,March 1964,272-285;Charles等,J.Clin.Invest.,Vol,76,December 1985 2254-2258;以及Deacon等,Clin.Chim.Acta.,1987,297-306.Pyridinoline和Deoxy-Pyridinoline为骨中存在的两种胶原交联物,它们可在尿中检测到,同样也可作为骨吸收的标记。Robins,等,European Journal of Clinical Investigation(1991),21:310-315.
血清骨蛋白的浓度用作骨形成率的生化标记。骨蛋白是骨形成过程中由骨形成细胞(成骨细胞)合成的有机骨基质的膜内在蛋白。少量新合成的骨钙蛋白逸入循环***,因而提供了骨形成率的血标记。骨钙蛋白的浓度随着骨形成率的增加而增加,随着骨形成率的降低而降低。Broun等,TheLancet,May 19,1984,p.1091,″Serum Bone GLA-Pro-tein:A Specific Marker For Bone Formation in Post-menopausal Osteoporosis″。骨吸收/骨形成的另一反映为和磷平衡的变化(阳性或阴性),这种变化通过测量总***量(粪便和尿)与规定食物或磷离子的吸入量间的差别来测定。(当总***量少于规定食物的吸入量时这种平衡为阳性)。
对于绝经后的妇女,***不足已被确定为骨质疏松的主要素因性因素。已有报告称长期***替代疗法可能引起绝经后妇女骨质疏松更加严重。Johansen,等(1990)Metabolism Vol.39,No.11,pp.1122-1126;Ettinger,Ob-stetrics & Gynecology,(1988),72:125-175:Ettinger等,Annals of Internal Medicine(1985),102:319-324。
已被FDA批准且对骨质疏松的防治或治疗有效的***的最小剂量为0.625mg结合***,或其它***的等效剂量。然而,长期以这种水平服用***会造成严重的健康危害。三组独立的研究已表明绝经后的妇女以上述剂量水平长期服用外原***患子宫内膜癌的危险性增大。Siel,等(1975)New England Journal of Medicine,293:1167-1170;Smith等(1975)New England Journal ofMedicine,293:1164-1167;Mack等(1976)New EnglandJournal of Medicine,294:1262-1267。这三组研究报道了***使用者患子宫内膜癌的危险性大于不服用者4.5至13.9倍。这种危险性仿佛既与治疗的持续时间有关,Ziel等,同前,又与***的剂量有关,Mack等,同前。
除证明的***疗法中子宫内膜癌的危险性外,至少还有一种研究表明绝经后的妇女服用***有增大患***癌的危险性。New England Journal of Medicine(1974)290:15-19。还有报告报道了绝经后接受***的妇女患外科性固定胆囊疾病的危险性增加二至三倍。同前。此外,接受***治疗的绝经妇女患血栓栓塞和血栓血管疾病和高血压的危险性增加。Pfeffer等,(1976)Am.J.Epidemiology103:445-456。因而,在有效治疗骨质疏松需要的剂量水平下,***可能造成严重的健康危害和副作用。
一类研究表明将孕激素结合到***替代疗法中能提供免患***诱发的子宫内膜癌的保护作用并可以改进骨代谢。Williams等(1990)Am.J.Obstet.Gynecol.,Vol.162,pp.438-446。然而,促孕剂的加入能引起副作用的高发生率,这些副作用包括每月一次出血及经前症状。同前。尽管上述研究表明这些副作用可通过下述给药方式减缓:与接序周期方式给用***和孕激素相反采用持续每日方式与***结合给用孕激素的施药。但上述研究表明65个接受持续剂量***和孕激素剂量的病人中有3人生长有子宫内膜息肉。同前。
另一研究,Ettinger,(1988),Obstetrics & Gynecology72:125-175,建议通过增大病人的钙吸入量到至少1500mg/天,钭用于治疗骨质疏松的***的通常剂量,即约0.6mg上述结合***减少一半。然而,该研究暗示即使***通常剂量的一半也很有可能引起月经出血以及其它不需要的副使用。
1992年10月15日授权的美国专利5,171,583(该申请的内容可列于本文中作为参考)公开了对害有或患有骨质疏松症病人的骨质疏松症的改善或治疗方法,包括给用含有治疗或预防有效量的可药用的碱化钾盐混合物的组合物。其中公开的碱化钾盐的有效剂量为40-400mmoles/70kg病人体重/天,优选40-250mmdes/70kg/天。
本发明的目的之一是提供一种比单独使用***治疗更有效的治疗骨质疏松的方法和组合物。
本发明的另一目的是提供一种治疗骨质疏松的方法和组合物,它能减轻要不则消除用***治疗所伴随产生的危害和副作用。
本发明涉及一种新的改善或治疗害有或患有骨质疏松症病人的骨质疏松的方法,该方法包括给用下列活性成分的组合物:
(a)可药用的碱化钾盐,该盐可产生羟基离子并因而能降低组织液或尿液的酸性(通过增强碱性),且所述盐选自碳酸氢钾和能在体内转化(燃烧)成碳酸氢盐并因此可碱化的羧酸的钾盐;和
(b)对骨质疏松的治疗有效的***,所述***可以以小至其正常推荐剂量的1/10的量,优选以约1/10正常推荐剂量至推荐剂量或更大量的剂量给药;
碱化钾以下述量给药:该剂量能使两种药物的结合给药实质上更有效,通常比用相同量的***单独给药治疗骨质疏松时更有效10%至高达50%,或者更高。
本发明可药用的碱化钾盐与***的结合给药在治疗骨质疏松时所产生的协同效应在本发明之前对本专业技术人员是非显而易见的。因此,本发明提供了比常规***治疗骨质疏松更有效的治疗方法。此外,如果需要,根据本发明,联合用药中所施用的***的量可低至1/10如下定义的***的正常推荐剂量。本发明较低剂量的***与碱化钾盐结合的组合物对骨质疏松的治疗更有效。并能带来减轻要不则消除用***常规治疗所伴随产生的健康危害和副作用的明显好处。碱化钾盐与***的一同使用可以避免***与孕激素共用药的危害;另一方面,碱化钾盐的促尿钠***特性可以平衡孕激素的钠——保留性质,因而能提高结合***-孕激素-碱化钾治疗所得的结果。
本发明结合药物的活性成分,即(a)可药用的碱化钾盐和(b)对骨质疏松治疗有效的***可以以相互结合的单独剂型(Seperate doseage form)给药,即以相同或按不同的时间表给药。另一方面,如下更充分的描述,优选将碱化钾盐与***混合成单元剂型,该剂型给用时避免了需要分别给用这些活性成分。
本文中所用术语“治疗”或“医治”包括任何骨质疏松病的治疗,且包括:(1)预防骨质疏松在未患有骨质疏松症的宿主或仍未被诊断有骨质疏松症的宿主体内出现;(2)抑制或阻止疾病的发展;或(3)退化或逆转骨质疏松状态。
本文所述的术语“正常推荐剂量”,当用于***时,意指对患有骨质疏松的病人给用能有效治疗骨质疏松的***的量,即它能在人体内引起下列效应:
(a)降低尿羟基脯氨酸***率;
(b)降低尿胶原交联***率;和
(c)增强钙和磷平衡,即使它们呈较弱的阴性和较强的阳性。例如,在骨质疏松的治疗中,已知的如结合***(定义如下)的***的正常推荐剂量为0.625mg,按周期性方式给药,即给药三周,停药一周。参见Pysicians Desk Reference,1993版,P2624…25。(上述效应无论***是否与孕激素同时给用均产生)。
如本文所用,“当单独给药时相同剂量的所述***”是指本发明结合药物中相同***的相同量,在这种情况下仅给用***而不再给用本发明结合药物的碱化钾盐成分。
如本文所用,术语“胶原交联物”是指Pyridenoline和deoxy-pyridinoline交联物。
如本文所用,术语“钙平衡”是指钙总***量(粪便和尿)与规定食物钙吸入量间的差值。同样,术语“磷平衡”是指磷总***量(粪便和尿)与规定食物磷吸入量间的差值。
在本发明方法中可采用的碱化钾盐是指当存在于人体体液中能产生羟基离子,因而能降低组织液或尿酸性(增强碱性)的碱化钾盐。大量可药用的碱化钾盐是已知的,其中几种见Berg等,J.pharmaceut.Sci(1977)66:1中所述,该文献可并入本文作为参考。倘若上述文献公开于此,本专业技术人员很容易通过采用已知方法和技术选择和筛选出能够用于治疗骨质疏松的可药用的碱化盐。最好所选择的盐应是有治疗活性的,人体内易被接受的且具有相对较好的容忍性。根据特定的给药途径以及优选的制剂方式可选择不同的盐。
可如此给药的碱化钾盐优选选自碳酸氢钾(KHCO3)和可药用,无毒的羧酸钾盐如葡萄糖酸钾(C6H11KO7)和柠檬酸钾(C6H5K3O7)。特别优选使用碳酸氢钾。这些盐的制备,例如它们通常在具有众多治疗背景的用途而非本文所描述的用途方面使用。制备这类盐的特殊方面法一般地见Remington′s Pharmaceutical Sciences,Mack PublishingCompany,Easton,Pennsylvania,16th Ed.,1982,该资料可列于本文作为参考。
其中R1为羟基且R2选自H,-C=C,以及-C≡C,或者
R1和R2一同表示通过双键与分子键合的氧,
R3或者为氢或者为羟基,以及
R4选自H,甲基,以及环戊基,和
其中所述***或者在6-7和8-9位具有双键,在7-8位具有双键,或者在6,7,8和9的位置无双键。
例如本发明能给用的***包括但不局限于所有下述***和它们的混合物:雌甾酮(3-羟基雌-1,3,5(10)-三烯-17-酮);17β-***(17β-雌-1,3,5(10)-三烯-3,17-二醇);17α-***(雌-1,3,5(10)-三烯-3,17α-二醇);炔雌醇(17α-乙炔基-1,3,5(10)-雌三烯-3,17β-二醇);马烯雌酮(3-羟基雌-1,2,5(10),7-四烯-17-酮);去氢马烯雌酮(3-羟基雌-1,2,3,5,7,9-五烯-17-酮);17α-二氢马烯雌酮(17 α-雌-1,3,5(10),7-四烯-3,17-二醇);17β-二氢马烯雌酮(17β-雌-1,3,5(10),7-四烯-3,17-二醇);17α-二氢去氢马烯雌酮(17-雌-1,3,5,7,9-五烯-3,17-二醇);17β-二氢去氢马烯雌酮(17β-雌-1,3,5,7,9-五烯-3,17-二醇);炔雌醚甲醚(17-α-乙炔基-3-甲氧基-1,3,5(10)-雌三烯-17β-醇);雌三醇环戊醚(雌三醇3-环戊基醚);炔雌醚(17α-炔雌醇环戊醚);苯甲酸***(17β-雌-1,3,5(10)-三烯-3,17-二醇3-苯甲酸酯);17β-环戊丙酸***(17β-雌-1,3,5(10)-三烯-3,17-二醇17-环戊丙酸酯);以及结合***。
如本文所述,本语“结合***”是指由自然资源中得到的以水溶性***硫酸酯的钠盐形式存在的结合***的混合物,所述硫酸酯是代表来自妊娠母马尿液中的物质的混合平均组分,其主要成分为雌甾酮硫酸酯。结合***是由Wyeth-Ayerst Laboratories以“PREMARIN”商标出售。参见Physicians Desk Reference,1993 Edition,P2624-26。
前述各种***的制备,分离和纯化对本专业技术人员而言是已知的。已有大量文献描述了如何制备这些***,且这些文献以前述***的标题被Merck Index(11th Ed.1989)引录。Merk Index及其所引用的叙述制备这些***的文献可并入本文中作为参考。
本发明可药用的碱化钾盐或***成分的给药可以为下文所描述的药用组合物形式并可以通过已知的骨质疏松治疗中使用的药剂的任何可接受的给药方式给用。对于碱化钾盐,这些方法包括口报,非肠道给药,以及其它***给药方式。不同的碱化钾盐可以混合并同时给用,或者在某些情况,分离,有序给用它们可能获得一些益处。对于***,这些方法包括口服,非肠道给药,经皮给药,以及其它***给药方式。
依据预定给药方式,碱化钾盐成分可以为固体,半固体或液体剂量形式,如,片剂,胶囊,丸剂,粉剂,粒剂,晶体,液体,悬浮剂等剂型,优选适合具有相对准确剂量给药的单位剂量形式。同样,***成分可以是固体片剂,胶囊或丸剂的形式,优选为适合具有相对准确剂量给药的单位剂量形式。
优选的是将碱化盐和***成分结合成片剂,胶囊或丸剂的单元固态剂型,因而消除了分别给用这些成分的需要。固态结合剂型可以包括常规药学载体或赋形剂,而且还可包括其它药剂。因而,单位剂型可与常规无毒固体载体结合,所述载体例如为药用级别的甘露醇,乳糖,淀粉,硬脂酸镁,滑石,纤微素,葡萄糖,蔗糖,碳酸镁等等。这种组合物可以含有约50-90%本发明的活性成分,优选70-90%。
另一方面,碱化钾盐成分可以与***活性成分给药结合的单独剂量形式给药。因而两种药物根据它们通常的给药方式可以以相同的计划表或不同的计划表给药。当碱化钾盐成分以单独剂型给用,它可以是片剂,丸剂,胶囊,粉剂,粒剂,晶体,持续释放剂型等并含有任何前述赋形剂的形式,或者以液态药学上可施用的组合物形式给用。这种液态组合物可通过例如将盐,如碳酸氢钾以及任选的药物辅剂溶于如水,葡萄糖水溶液,甘油等载体内来制备,因而形成溶液或悬浮液。如果需要,单独的碱化盐剂型还可含有少量无毒性辅助物质如pH缓冲剂等,例如,去水山梨糖醇单柠榈酸酯,三乙醇胺,乙酸钠,三乙醇胺油酸盐等。制备这种剂型的现行方法是已知的,或者对本专业人员是显而易见的;参见前述的Remington′s Pharmaceutical Sciences,Mack PublishingCompany,Easton,Pennsylvania,16th Ed.,1982。结合药物的活性钾盐成分如碳酸氢钾例如可以丸剂,直接施加到食物的粒剂和粉剂供给的食物补充方式提供,或溶于饮用水中以常规给药方法的形式提供。
本发明结合药物的***成分可以小至1/10正常推荐剂量的量给用。本发明结合药物的碱化钾盐成分以下述剂量给用。该剂量是结合药物比单独给用相同量***治疗骨质疏松时更有效10%,或者高达50%或更高。
作为优选,***成分口服给用的量等效于(基于每日剂量)0.06至1.25mg,优选0.06至0.625mg结合***。结合药物中碱化钾盐的给用量为30-120,优选30至60毫当量。在这些水平下,与单独给用相同量***时的结果相比,可观察到下列相对结果:
(a)尿羟基脯氨酸***率的降低(按Klein,Charles等和Deacon等的上述文献中所述方法测量)超过10%;
(b)尿胶原交联***率的降低(按Robins等的上述文献所述方法测量)超过10%;以及
(c)钙和磷平衡的增加(按常规方法测量)例如高至10%,或更高。
正如从前面所看到的,本发明活性成分的结合物在治疗骨质疏松中显示出协同效应,即两种药物的结合比单独给用相同量***实质上更有效。最优选的是***可以以等同于口服给用低至0.06mg结合***的量给药。当在本发明结合中使用时,***的最低剂量不仅对治疗骨质疏松是有效的,而且能显著降低使用常规剂量***所伴随产生的健康危害和副作用。
按照本发明给药的***成分的量当然依赖于所使用的特定***的效力以及给药方式。各种***的相对和相等效力是本专业技术人员熟知的。例如,依据***治疗骨质疏松的效力和能力,0.6mg结合***等效于2.0mg微粉化的17β-***。将这些公开列于本文中,本专业技术人员很容易选择等效于本文所述的***和剂量水平的***和剂量水平。
本发明结合药物可以以每日连续方式给药,或者代之以以周期方式给药,即三周用药,一周停药。同样本专业技术人员可以理解除给用本发明所描述的结合药物外,最好还应补充病人的钙吸入量,如果需要,每天保持吸入1500mg钙。
下述实施例说明了本发明的一些特别优选,非限制性的方面
实施例I
制备含有下述活性成分的结合药物片剂:0.156mg结合***和1.5g碳酸氢钾。每日适合给用四片这类片剂。
实施例II
制备含有与实施例I相同成分的结合药物片剂并按相同方案给药,只是每片中仅含有0.08mg结合***和0.75g碳酸氢钾。
按照前述内容,应当理解本发明提供了一种新的有效治疗/预防人骨质疏松的方法和组合物,且与常规激素治疗骨质疏松方法相比具有较低的健康危害和副作用发生率。
为了清楚理解本发明,尽管本发明已通过说明和实施例相当详细地进行了描述,但在附加的权利要求范围内进行的一些变化和改进都是显而易见的。
Claims (14)
1.用于治疗患有骨质疏松病人的骨质疏松症的两种药物结合药物,包括
(a)能够降低组织液或尿液酸性的可药用的碱化钾盐,所述碱性钾盐选自碳酸氢钾和在体内可碱化的羧酸钾盐;和
(b)对骨质疏松治疗有效的***,其量为少至其标准推荐量的1/10;
碱化钾盐以下述量存在:该用量使得结合药物比单独施用相同量所述***治疗骨质疏松时实质上更有效。
2.权利要求1的结合药物,其中所述***包括具有下述通式的化合物,包括其可药用的盐和酯:
其中R1为羟基,R2选自H,-C=C,以及-C≡C,或者
R1和R2一同表示通过双键与分子键合的氧,
R3或为氢或为羟基,
R4选自H,甲基和环戊基,以及
其中***或者在6-7和8-9位具有双键,在7-8位具有双键,或者在6,7,8和9位无双键。
3.权利要求2的结合药物,其中碱化钾盐和***以下述比例量掺合:碱化钾盐日剂量为30-120毫当量且***的日剂量等效于0.06至1.25mg结合***。
4.权利要求3的结合药物,其中碱化钾盐以下述量存在,该量使得结合药物能够:
a.与单独给用相同量所述***时受治者的尿羟基脯氨酸***率相比,能降低受治者尿羟基脯氨酸***率超过10%;
b.与单独给用相同量所述***时受治者的尿胶原交联物***率相比,能降低受治者尿胶原交联物***率超过10%;以及
c.增加受治者的钙和磷平衡。
5.权利要求4的结合药物,其中所述的碱化钾盐和***混合成可进一步包含其可药用载体的单位剂型。
6.权利要求5的结合药物,其中所述的碱化钾盐为碳酸氢钾。
7.治疗患有骨质疏松疾病病人的骨质疏松病的方法,包括给用下列活性成分的结合药物:
(a)能够降低组织液或尿液酸性的可药用碱化钾盐,所述钾盐选自碳酸氢钾及在体内能碱化的羧酸的钾盐;和
(b)对骨质疏松治疗有效的***,其量为少至其标准推荐量的1/10;
碱化钾盐以下述量被给用:该量使得结合药物比单独施用相同量所述***治疗骨质疏松至少更有效10%。
9.权利要求8的方法,其中碱化钾盐每天以30-120毫当量的量给药,***以等效于0.06至1.25mg结合***的量给药。
10.权利要求9的方法,其中碱化钾盐以下述量给药,该药使得活性成分的结合药物的给药具有:
a.与单独给用相同量所述***受治者的尿羟基脯氨酸***率相比,能降低受治者尿羟基脯氨酸***率超过10%;
b.与单独给用相同量所述***受治者的尿胶原交联物***率相比,能降低受治者尿胶原交联物***率超过10%;以及
c.与单独给用相同量所述***受治者的平衡相比,能增加受治者钙与磷平衡超过10%。
11.权利要求9的方法,其中碱化钾盐和***以单独剂型给药。
12.权利要求9的方法,其中碱化钾盐和***以单元剂型给药。
13.权利要求11的方法,其中单元剂型还进一步包含可药用的载体。
14.权利要求9的方法,其中碱化钾盐为碳酸氢钾。
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JP (1) | JPH08508502A (zh) |
KR (1) | KR960701642A (zh) |
CN (1) | CN1120314A (zh) |
AU (1) | AU692155B2 (zh) |
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CA2534577A1 (en) * | 2003-08-06 | 2005-02-24 | Rhodia, Inc. | Method for promoting bone growth |
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US3608077A (en) * | 1969-11-13 | 1971-09-21 | Syntex Corp | Stabilization of metal steroid alcohol sulfates |
US4078060A (en) * | 1976-05-10 | 1978-03-07 | Richardson-Merrell Inc. | Method of inducing an estrogenic response |
US4261985A (en) * | 1978-11-22 | 1981-04-14 | Ciba-Geigy Corporation | Novel diuretics |
US4617298A (en) * | 1985-10-22 | 1986-10-14 | University Of Florida | Method and compositions for weight control |
US4814177A (en) * | 1986-03-18 | 1989-03-21 | Board Of Regents, University Of Texas System | Ultradense and more soluble and bioavailable preparations of calcium citrate |
US5171583A (en) * | 1988-10-21 | 1992-12-15 | The Regents Of The University Of California | Treatment of osteoporosis using potassium bicarbonate |
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KR960701642A (ko) | 1996-03-28 |
EP0692965A4 (en) | 1998-08-12 |
CA2159354A1 (en) | 1994-10-13 |
AU692155B2 (en) | 1998-06-04 |
WO1994022457A1 (en) | 1994-10-13 |
AU6621994A (en) | 1994-10-24 |
BR9406101A (pt) | 1995-12-19 |
JPH08508502A (ja) | 1996-09-10 |
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