CN1062735C - 双磷酸衍生物用于制备促进骨修复药物的应用 - Google Patents
双磷酸衍生物用于制备促进骨修复药物的应用 Download PDFInfo
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Abstract
本发明涉及式(Ⅰ)的双磷酸衍生物及其用可药用无机或有机酸成的盐用于制备在人或兽医疗中促进骨修复药的应用,其中,R1和R2基团的定义见说明书。
Description
本发明涉及双磷酸衍生物用于制备在人或兽医疗中促进骨修复药物的应用。
骨修复的生理学过程被定义为持续出现不同的瘢痕组织;它们按下面顺序出现:软骨,初级骨(非组织的),然后片层骨(组织的)。它们每个仅在前面一个损坏之后形成。这种变化因此归因于一种吸收作用,它由巨噬细胞保证:破软骨细胞完成软骨吸收作用而破骨细胞完成骨吸收作用。在L.Teot,J.Vidal和J.Dossa指导下编辑的Le Tissu Osseux(骨组织)中收集物:Biologie del'appareil locomoteur(运动器官生物学),DiffusionVigot,1989和H.M.Frost著的《骨折治疗生物学》中清楚地描述了上述变化。还有一篇对临床医师的综述Ⅰ和Ⅱ,Clin Orthop.,1989,248,283等。
在随后的说明和权利要求中,双磷酸衍生物被理解成式Ⅰ化合物和用可药用无机或有机酸成的盐其中:-R1是氢原子,卤原子,羟基,氨基,单-C1-C4-烷基氨基或二-C1-C4-烷基氨基;且-R2是卤原子或含1到5个碳原子的直链烷基,它是未取代的或被选自氯原子,羟基,氨基,单-C1-C4-烷基氨基,二-C1-C4-烷基氯基和C3-C7-环烷基氨基的基团取代,或R2是苯氧基,苯基,硫羟基,苯基硫代,氯苯基硫代,吡啶基,吡啶基甲基,1-吡啶基-1-羟基甲基,咪唑基甲基或硫代吗啉-4-基。
这些化合物是已知的且在治疗骨疾病中作为药物已被描述,尤其在下面专利中:BE 902308,BE 865434,DE 2130794,US 4134969,EP 162510,FR 2525223,EP 39033,US 4578376,EP 203549,BE 822930,US 4621077,JP 55-98193,EP 186405,EP 1007,WO 86/00902,WO 87/03598,US 4922007,EP 304961,JP 63-150291和EP 325482。
在这些双磷酸衍生物中尤其可提到下面化合物:-1-羟基亚乙基双磷酸,具有国际非专利名羟乙二磷酸,及其钠盐;-2-吡啶-2-基亚乙基双磷酸,国际非专利名为Piridronicacid,及其钠盐;-二氯亚甲基双磷酸,国际非专利名为clodronic acid,及其钠盐;-3-氨基-1-羟基亚丙基双磷酸,国际非专利名为pamidronicacid,及其钠盐;-4-氨基-1-羟基-亚丁基双磷酸,国际非专利名为alendronic,acid,及其钠盐;-6-氨基-1-羟基亚己基双磷酸及其盐;-苯氧基亚甲基双磷酸及其盐;-硫代吗啉代亚甲基双磷酸及其盐;-4-氯苯基硫代亚甲基双磷酸,国际非专利名为tiludronicacid,及其可药用盐,尤其是二钠盐;-1-羟基-2-(吡啶-3-基)亚乙基双磷酸,国际非专利名为risedronic acia,及其钠盐;-1-羟基-2-(咪唑-2-基)乙基-1,1-双磷酸及其盐;-(环庚基氨基)亚甲基双磷酸及其盐;和-2-羟基亚乙基-2-(吡啶-3-基)-1,1-双磷酸及其钠盐。
上述双磷酸衍生物一般指双磷酸盐。
按照本发明,使用tiludronic acid及其可药用盐,尤其是二钠盐,是尤其优选的。
双磷酸衍生物的生物学作用是通过减小破骨细胞的活性来抑制骨吸收作用,如下面出版物所述:
-H.Fleisch,R.G.G.Russel和M.D.Francis:双磷酸盐在体外抑制羟基磷灰石的溶解,在组织培养基和体内抑制骨吸收;Science,1969,165,1262-1264;
-P.M.Boonekamp,L.J.A.Van der Wee-Pals,M.M.L.Van Wijk-Lennep,C.W.Thesing和O.L.M。Bijvoet:双磷酸盐对破骨细胞吸收矿化基质作用的两种方式;Bone Miner.,1986,1,27-39;和
-A.M.Flanaghan和T.J.Chambers:二氯亚甲基双磷酸盐(Cl2,MBP)通过损伤吸收涂渍ClMBP骨的破骨细胞来抑制骨吸收;Bone Miner.,1989,6,33。
几种双磷酸衍生物目前正在开发用于治疗人体疾病或销售用于治疗骨疾病如Paget's疾病和骨质疏松症。这些疾病的特征是破骨细胞刺激(对Paget's疾病比对骨质疏松症更显著),它必须被制止。
H.C.Tennenbaum等在Bone,1992,13,249-255,中发表的一篇文章涉及到在体外给入低剂量双磷酸盐后骨生成的酶标记物的增加。
Feretti等在Bone Miner.,1990,11,111-122中发表的一篇文章谈到了体外给入双磷酸盐后观察到的骨生物机械性能的改进,骨质没有增加。
而且,由于双磷酸盐抑制骨吸收且由于吸收步骤在随骨折或骨手术之后发生的骨修复方法中是必需的。本来并不期望给入双磷酸盐对骨修复具有有益作用;相反,对于骨修复来说双磷酸盐可能被预料是相反的作用,因此可以引用F.Bonnel和B.Tachot:在Le TissuOsseux(相反引入:在L.Teot,J.Vidal和J.Dossa指导下编辑的收集物:Biologie de l'appareil locomoteur,Diffusion Vigot,1989)中Biologie de lacicatrisation Osseuse des fractures(骨折中骨治疗生物学):“双磷酸盐,它们具有制止破骨细胞吸收作用且总体上说抑制骨改型。对骨折来说,愈合前必须把它们取出”。
然而,本发明人完全意外地发现双磷酸衍生物对骨修复,尤其是对促进骨修复是有用的。
因此,本发明涉及双磷酸衍生物用于制备促进骨修复,尤其是骨折或骨手术后骨修复药物的应用。
这类药物可用于人和兽。
这类药物可通过不同给药方式给药,例如口服,非肠道,透皮或通过植入法。
当制备用于口服给药的药物时,可以便用任何适当的赋形剂,且尤其是促进药物吸收的赋形剂如十二烷基硫酸钠。
本发明药物的给药剂量取决于所用的双磷酸衍生物,给药方式和对骨修复所需作用的大小。
本发明的药物可作为单剂量或多次剂量给药。对多次剂量给药来说,可以在整个骨折修复期间内选择每日连续给药,每天1到3次,或间歇给药,例如在1到数月内一周给药一天。
剂型可以包括0.001mg到400mg,尤其是0.01mg到400mg式Ⅰ双磷酸衍生物。
因此,按本发明制备的药物的给药剂量可在每天0.001mg到1.2g,尤其是每天0.01mg到1.2g的范围内变化。
剂型优选包括0.1到250mg式(Ⅰ)的双磷酸衍生物。
对口服给药来说,本发明的药物组合物可以呈片剂,胶囊,粉剂,粒剂,滴剂形式或任何其它适于口服给药的形式。
本发明的组合物也可以含有通常用于制备口服剂型的药剂学的组分。因此本发明的组合物可以含有崩解剂,助流剂,润滑剂和任何适当的大量赋形剂。
可以使用的大量赋形剂是乳糖,纤维素或淀粉。可以使用的润滑剂是硬脂酸,硬脂酸镁,L-亮氨酸,或例如甘油三山萮酸酯。可以使用的崩解剂是羧甲基淀粉钠,交联的羧甲基纤维素钠,或例如交联的聚乙烯吡咯烷酮。可以使用的助流剂是纯硅石或胶体二氧化硅。
本发明进一步涉及瞬时溶解的口服剂型和通过把起泡对加入本发明的组合物中得到的泡腾口服剂型。可以使用的起泡对的实例是酒石酸和碳酸氢钠或柠檬酸和碳酸氢钠。
片剂形式是本发明的优选形式。本发明进一步涉及瞬时溶解的片剂,泡腾片剂和包衣片剂。按照欧洲专利EP 336851,含十二烷基硫酸钠的组合物是尤其适当的。
对于口服给入tiludronate来说,单位剂量从0.05mg到1000mg,优选从0.05mg到400mg,更尤其是从0.1mg到250mg之间变化。
对口服给入Pamidronate或etidronate来说,单位剂量从0.05mg到1g,优选从0.05mg到400mg之间变化。
对口服给入alendronate,risedronate或(环庚基氨基)亚甲基双磷酸或其一种盐来说,每日给药剂量从0.001mg到100mg,优选从0.01mg到100mg之间变化。
使用水相的悬浮液,等渗盐水溶液或可能含药理上相容的分散剂和/或润湿剂如丙二醇或丁二醇的消毒和可注射溶液,进行非肠道给药。
对透皮给药来说,本发明的组合物可以呈乳膏,软膏形式或透皮给药的组合物形式。
实施例1:骨修复的测量
使用半骨切开术模型对狗进行骨修复实验研究。
半骨切开术的原则是沿着属于双桡骨的长骨(尺骨)的骨干产生不完整的骨折线。此半骨折因此被相同骨的未骨折部分和另一骨稳定,避免使用任何固定设备。
使用每组由4条雄性Beagle狗组成的三个组;半骨切开术后六周内(0天到45天)通过管饲法分别对它们进行每天处理一次。把产品以胶囊的形式给入。
表1
组 | 动物数 | 产品 | 剂量(mg/kg) |
1 | 4 | 载体(空胶囊) | - |
2 | 4 | tiludronte | 5 |
3 | 4 | etidronate | 10 |
相隔数天分两次给入四环素以便标记在不同时间26天和27天及随后的41天和42天的矿化线。
在半骨切开术后45天时,杀死动物。将进行半骨切开术的骨移开并固定以便进行下面组织形态测定:
-测量每mm2破骨细胞数;
-测量吸收的活性面积(%):此面积是相对于总面积被破骨细胞占据的面积;此测量便骨吸收得以评价;
-测量相对于总骨面积双标记的面积(%):此测量使层骨得以定量;和
-测量小梁体积(TV),表示成总骨体积(BV)的百分数;在由半骨切开术造成的破裂处,此体积代表形成骨的量,包括骨样边和矿化组织。
在半骨切开术后45天,通过分析共振频率也进行生物机械测试:在纵向面内的尺骨上测量共振频率,通过放在骨上面1cm处的传声器记录振动,用锤碰撞尺骨中间进行刺激。信号传到光谱分析器,它给出光谱频率,然后测定共振频率。
对记录信号计算4种测量的平均值。以这种方式评价两个参数:
1)骨硬度:评价骨对纵向面内振动的耐力。
计算的硬度是F2M(Hz2xg)。
F:共振频率(赫兹)。
2)翘曲强度:计算对抗纵向面内振动的力。翘曲强度是F2ML(Hz2xgxmm)。
L:长度(mm)
结果(平均值和均方根误差:r.m.s,error)列于下表:
表2
组(产品) | 每mm2破骨细胞数(r.m.s.error) | 吸收的活性面积(%)(r.m.s.error) | 双标记的面积(%)(r.m.s.error) |
组1(对照)组2(tiludronate)组3(etidronate) | 8.19(1.19)9.54(1.73)5.58(0.92) | 3.32(0.35)5.44(0.61)4.95(0.18) | 2.21(1.48)20.55*(2.96)6.49(4.12) |
*:P<0.05
结果清楚地表明对两种双磷酸盐来说最后片层骨量增加,而骨吸收参数没有发生同时改变。
表3
组(产品) | 骨小梁体积BV/TV%(r.m.s.error) | 骨硬度Hz2xg(r.m.s.error) | 翘曲强度Hz2xgxmm(r.m.s.error) |
组1(对照)组2(tiludron-ate)组3(etidronate) | 65.6(2.6)70.4(0.9)60.3(6.2) | 85.9(16.9)157.4(26.7)110.8(25.9) | 101.8(17.1)192.8(32.5)135.4(34.1) |
这些结果表明在用双磷酸盐处理后:
-处理没有使骨小梁体积显著减小,和
-生物机械性能得到改进;事实上,骨硬度和翘曲强度增加,尤其是用tiludronate时。实施例2:增进骨修复的片剂
可分片剂:
-相当于200mg酸,tiludronic acid二钠盐240mg
-十二烷基硫酸钠 4.5mg
-交联的羧甲基纤维素钠 24mg
-微晶乳糖 177mg
-硬脂酸镁 4.5mg
450mg
实施例3:增进骨修复的片剂
可分片剂:
-相当于50mg酸,tiludronic acid二钠盐 60mg
-十二烷基硫酸钠 3mg
-交联的羧甲基纤维素钠 6mg
-无水乳糖 44.25mg
-硬脂酸镁 1.25mg
114.5mg实施例4:增进骨修复的片剂
-相当于25mg酸,tiludronic acid二钠盐 30mg
-交联的羧甲基纤维素钠 3mg
-硬脂酸镁 0.75mg
-微晶乳糖 22.25mg
56mg实施例5:增进骨修复的可注射溶液
-etidronic acid二钠盐 300mg
-注射制剂用水
6ml实施例6:增进骨修复的灌注剂
-sodium pamidronate的冷冻干燥物 15mg
-注射制剂用水 6ml实施例7:增进骨修复的灌剂
-clodronic acid的二钠盐 300mg
-氢氧化钠 qsP pH5
-注射制剂用水
5ml
Claims (6)
1.4-氯苯基硫代亚甲基双膦酸-其国际非专利名为替鲁膦酸、羟乙二膦酸-其国际非专利名为依替膦酸,或它们的可药用盐用于制备促进骨修复药物的应用。
2.按照权利要求1的应用,用于制备口服给药的药物。
3.按照权利要求1的应用,用于制备透皮给药的药物。
4.按照权利要求1-3中任何一个的应用,其中药物含0.001mg到400mg所述化合物。
5.按照权利要求1-3中任何一个的应用,其中药物含0.1mg到250mg所述化合物。
6.按照权利要求1的应用,其中其可药用盐是钠盐。
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-
1993
- 1993-04-05 FR FR9303999A patent/FR2703590B1/fr not_active Expired - Fee Related
-
1994
- 1994-03-29 AU AU59102/94A patent/AU680229B2/en not_active Expired
- 1994-03-30 NO NO941185A patent/NO305304B1/no not_active IP Right Cessation
- 1994-03-31 NZ NZ260244A patent/NZ260244A/en not_active IP Right Cessation
- 1994-04-01 DE DE69428827T patent/DE69428827T2/de not_active Expired - Lifetime
- 1994-04-01 ES ES94400719T patent/ES2166771T3/es not_active Expired - Lifetime
- 1994-04-01 DK DK94400719T patent/DK0623347T3/da active
- 1994-04-01 AT AT94400719T patent/ATE207752T1/de active
- 1994-04-01 PT PT94400719T patent/PT623347E/pt unknown
- 1994-04-01 EP EP94400719A patent/EP0623347B1/fr not_active Expired - Lifetime
- 1994-04-04 CN CN94103549A patent/CN1062735C/zh not_active Expired - Fee Related
- 1994-04-04 US US08/222,240 patent/US5488041A/en not_active Expired - Lifetime
- 1994-04-04 IL IL10921294A patent/IL109212A/en not_active IP Right Cessation
- 1994-04-05 HU HU9400967A patent/HU220764B1/hu unknown
- 1994-04-05 CA CA002120538A patent/CA2120538C/en not_active Expired - Lifetime
- 1994-04-05 ZA ZA942358A patent/ZA942358B/xx unknown
- 1994-04-05 JP JP6067466A patent/JP3062001B2/ja not_active Expired - Lifetime
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WO1986000902A1 (en) * | 1984-07-31 | 1986-02-13 | Leo Pharmaceutical Products Ltd. A/S | Derivatives of methylene-bisphosphonic acid, process for their preparation and a pharmaceutical composition |
EP0336851A1 (fr) * | 1988-04-07 | 1989-10-11 | Elf Sanofi | Composition pharmaceutique pour administration orale à base d'un dérivé d'acide diphosphonique |
Also Published As
Publication number | Publication date |
---|---|
HU9400967D0 (en) | 1994-06-28 |
NZ260244A (en) | 1997-06-24 |
EP0623347A1 (fr) | 1994-11-09 |
IL109212A0 (en) | 1994-07-31 |
DE69428827D1 (de) | 2001-12-06 |
NO305304B1 (no) | 1999-05-10 |
US5488041A (en) | 1996-01-30 |
FR2703590A1 (fr) | 1994-10-14 |
PT623347E (pt) | 2002-03-28 |
ZA942358B (en) | 1995-10-05 |
DK0623347T3 (da) | 2002-02-11 |
AU5910294A (en) | 1994-10-06 |
ATE207752T1 (de) | 2001-11-15 |
JP3062001B2 (ja) | 2000-07-10 |
CA2120538C (en) | 1999-02-23 |
CN1104091A (zh) | 1995-06-28 |
DE69428827T2 (de) | 2002-07-18 |
NO941185D0 (no) | 1994-03-30 |
AU680229B2 (en) | 1997-07-24 |
IL109212A (en) | 2001-07-24 |
HUT68310A (en) | 1995-06-28 |
CA2120538A1 (en) | 1994-10-06 |
NO941185L (no) | 1994-10-06 |
ES2166771T3 (es) | 2002-05-01 |
JPH0748261A (ja) | 1995-02-21 |
HU220764B1 (hu) | 2002-05-28 |
FR2703590B1 (fr) | 1995-06-30 |
EP0623347B1 (fr) | 2001-10-31 |
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