CN101239182B - 用于骨诱导蛋白的磷酸钙传递载体 - Google Patents
用于骨诱导蛋白的磷酸钙传递载体 Download PDFInfo
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- CN101239182B CN101239182B CN2008100096136A CN200810009613A CN101239182B CN 101239182 B CN101239182 B CN 101239182B CN 2008100096136 A CN2008100096136 A CN 2008100096136A CN 200810009613 A CN200810009613 A CN 200810009613A CN 101239182 B CN101239182 B CN 101239182B
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- calcium phosphate
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Abstract
本发明涉及用于骨诱导蛋白的磷酸钙传递载体。本发明提供一种用于治疗哺乳动物骨缺损的组合物。该组合物包含骨生成蛋白,作为载体的磷酸钙材料,以及有效用量的泡腾剂。还公开了配制这种组合物的方法和使用这种骨生成组合物治疗骨质疏松和/或骨质缺乏的骨的方法。
Description
本申请是申请日为2002年6月6日的发明创造名称为“用于骨诱导蛋白的磷酸钙传递载体”的中国专利申请(国家申请号为No.02815639.0,国际申请号为PCT/US02/17798)的分案申请。
技术领域
本发明涉及可用作骨诱导蛋白传递载体的含有磷酸钙的复合材料,本发明还进一步涉及生物相容的骨诱导复合材料,可被用于骨再生和骨增长,以及在骨折、牙齿植入、骨植入和修补等时用于组织修复和强化。
背景技术
在生物药剂学领域,许多研究者正致力于开发有效的可植入性载体,用于药物传递和其它的外科用途。这种载体必须是生物相容性的,并且还必须能够保护打算被传递的任何一种生物活性作用剂的活性。许多生物活性作用剂都是不稳定的,当它们被掺入进传递材料时容易丧失活性。蛋白质活性的保存已经成为特别困难的问题。
在药物传递研究领域,磷酸钙陶瓷由于已知它们具有良好的生物相容性和对蛋白质试剂的亲和性,已被研究作为潜在的传递载体(见例如,Ijntena等,国际药学杂志112:215(1994);Itoka3u等.J.Orth.Res.10:440(1992);shinto等,骨关节外科杂志74-B:600(1992);以及Uchida等,J.Orth.Res.10:440(1992)),这些材料的大多数是以预制、烧结的颗粒状或小块状羟基磷灰石形式呈现,这种预制品存在几个缺点,包括局限的适应骨骼缺陷的能力,特别是在块状材料的情况下;颗粒状材料不充分的结构完整性(它们未结合在一起);以及难以用块状的颗粒状材料对缺损的骨骼组织外形做植入模型。但是,特别棘手的问题是块状羟基磷灰石提供的结构支撑必须借助于机械手段被固定在适当的位置,这就大大地限制了它的使用和它的整形效果。并且,要将羟基磷灰石块料锯磨成适合于病人特定缺损的形状也是非常困难的。颗粒状材料可产生较好的整形效果,但是,这种材料具有非常有限的结构稳定性,在外科手术过程中和之后都难以保持。通常,所有这些制品都是通过高温烧结产生的陶瓷,并且不是单独的结晶体,而是它们具有熔合在一起的结晶界面。大多数陶瓷类型的材料一般说来功能上是生物不可吸收的(通常具有每年不超过大约1%的吸收率)。
以珊瑚为基础的多孔不可再吸收材料允许与骨交互生长,但是最终成为只有大约20%的骨,其余的80%作为疤痕组织存在。由Osteogen研制的HA RESORB是一种可吸收的羟基磷灰石形式,但它不是水泥。它呈颗粒状,不具粘性。HA RESORB是松散地面不是粘结地被填充在适当的位置。其广泛的用途在于,它可非常快地被骨取代。在牙齿材料行业,HAPSET是磷酸钙颗粒和可粘结性烧石膏(硫酸钙)的一种组合物。这种材料实际上不是羟基磷灰石,并且对于大多数生物学用途,它含有非常多的硫酸钙。这种组合物的硫酸钙成分是可再吸收的,但磷酸钙颗粒不可再吸收。
至少有一类磷酸钙组合物是用于形成羟基磷灰石的前体,并且是生物相容性的,它们具有在其它磷酸钙生物材料不可得到的二种独特性质:(1)自我硬化,形成具有足够强度、适合许多医学和牙科应用的团块,以及(2)在被植入骨中时,此材料可缓慢地被再吸收,并可完全被形成的新骨取代,而接受移植的组织不丧失容积或完整性。参见Brown和Chow的美国专利Nos.Re.33,221和Re.33,161,其中公开了磷酸钙再矿质化组合物和一种基于相同磷酸钙组合物的精细结晶非陶瓷可逐渐再吸收的羟基磷灰石材料的制备方法。
Constantg等(美国专利Nos 5,053,212和5,129,905)描述了一个实际上相同的磷酸钙系统,它由磷酸四钙(TTCP)和磷酸单钙(MCP)或它的单水合物形式(MCPM)组成。据报导此系统包括将MCP转化成磷酸二钙,它再与TTCP反应形成羟基磷灰石(HA),作为最终产物,HA是牙齿和骨的主要矿物成分。
另一种类型的磷酸钙组合物包含作为反应物的非晶体磷灰石磷酸钙,促进剂和水性流体,形成一种逐渐硬化的糊状物。见例如Lee等的美国专利Nos.5,650,176;5,676,976;5,683,461;6,027,742和6,117,456。此系统提供了一种生物活性陶瓷材料,它是生物相容性的,可生物再吸收,并且在室温下可长时间使用。这种生物活性陶瓷材料可在低温下成形,它是可成形的和/或可注射的材料,并进一步反应还可以硬化成具有高强度。这种生物活性陶瓷材料含有少量结晶磷灰石磷酸钙固体,其钙与磷的比例(Ca/P)与天然存在的骨矿物质相类似,并且具有与天然骨相似的刚性和断裂面粗糙度。此生物活性陶瓷复合材料是高度可生物再吸收的,并且它的生物可吸收性和反应性可以被调节,以便适合特定治疗和/或植入部位的要求。该材料可以被制备成可高生物再吸收和/或骨化的骨化,骨螺丝钉和其它固定物,以及包括兽医应用的医用部件。
再造外科的目的之一是能够使用病人自己的细胞或者生长促进蛋白,以新组织代替受损伤的组织。例如,研究者已竭力创建了一种软骨再生系统,其中是在使用多聚体支架的情况下将分离出的软骨细胞注射进入受损伤的区域(见例如Atala等,泌尿学杂志150:747(1993);Freed等,细胞生物化学杂志51:257(1993),以及其中引用的文献)。在进行骨修理的情况下已经研制出类似的种植支架系统,在此是将成骨细胞用于与多聚物或陶瓷支架连接(见例如Elgendy等,生物材料14:263(1993);Lshaug等,生物医学材料研究杂志28:1445(1994)。特别有意义的是骨诱导物质,例如骨形态发生蛋白(如重组人BMP-2),脱矿物质骨基质,转化生长因子(如TGF-β),以及已知诱导骨形成的各种其它有机物质。
已经设计出三种通常类型的以磷酸钙为基础的支架材料,特定地与种植的组合物一起使用。第一种类型的支架材料由预先形成的磷酸钙为基础的小颗粒组成,并有生物活性物质结合在其表面。一般来说,为了避免引发炎症反应要求较大的颗粒(理想地是100-1000μm)。但是,这种预先制成的大颗粒材料不容易通过小口径针头注射,而需要经皮注射。此外,可以只要将活性因子与预先形成的小颗粒混合,使之包被在颗粒表面,而不是使此活性因子被包埋或者分散在整个基质中。包埋活性因子,当基质被再吸收时将便于更多的生物分子受控释放。预先形成的颗粒材料通常难以操作和应用。而且,大多数预先形成的羟基磷灰石颗粒材料是通过烧结过程产生的,致使它们基本上不可再吸收。
用于种植组合物的第二种类型支架材料由可植入的多孔羟基磷灰石或磷酸三钙小块组成。可制备具有不同程度孔隙率的可植入多孔隙小块状材料,通常是使用控制了微粒尺寸的反应物的干燥混合物。增加孔隙率的其它方法包括化学的或物理学浸蚀和过滤。虽然它们通常都能提供充分的支撑,但是多孔隙块状材料具有几个显著缺点。首先,像上面所述的预制的颗粒状材料,块状支架没有包埋在整个体积中的骨诱导物质,因此会阻碍活性物质的受控释放。第二,可植入的块状材料不是可注射的,而因此需要更强烈的植入步骤。最后,重要的是,整体的块状材料在临床应用中可能阻碍骨形成的速度,而在这种情况下都希望加速愈合,先于愈合过程的正常时间。这种延迟可能是由于固体载体的缓慢再吸收,以及随后活性物质的延迟释放。整块基质的存在也可能妨碍细胞向骨折部位迁移和浸润。设想块状基质中,在孔隙之间包含相互连接的管道,新骨生长将取决于孔隙,并受到支架壁的限制,这样将限制新骨的形成。
第三种类型的支架材料包括磷酸钙水泥。不同于预先制成的颗粒材料和整体的块状材料,水泥是易于注射的,并且可以使骨诱导物质包埋在其整个体积中。但是,这种水泥倾向于形成本质上是微孔隙的整体凝集物。虽然对使用生物可降解的孔隙形成器的大孔隙模型已有描述(见例如PCT专利公报No.WO 98/16209,在此被引入作为参考),但是,这种水泥形成含有管道的整体支架结构,而不是微孔隙的颗粒结构,如上所述,这种整体结构将明显地限制新骨生长。
因此,尽管在此领域付出了相当大的努力,但仍然需要有一种可生物相容性的,易于再吸收的,并且不损害药物活性的药物传递载体。理想的是,这种载体应该是可注射的,有展延性使其能注射或植入进不同大小的断裂和损伤部位,并能促进生物活性物质均匀地分布于整个基质中,这样有利于活性物质的受控释放,最后当施加于手术或缺损部位时,应该能形成分立开的大颗粒。为了促进细胞迁移和渗入,分泌细胞外骨基质,并且为血管形成提供通道,理想的是形成颗粒状,颗粒状还可提供较大的表面面积,有利于再吸收和活性物质的释放,并可增加细胞与基质的相互作用。本发明解决了这些需要,提供了几种用于药物传递和组织修补的材料和组合物。
发明内容
在一个实施方案中,本发明提供了一种用于治疗哺乳动物骨损伤的组合物,它包含磷酸钙材料,有效剂量的泡腾剂,以及生物活性物质。磷酸钙材料可以是无定形的磷灰石磷酸钙,羟基磷灰石,磷酸三钙或氟磷灰石。在优选的实施方案中,磷酸钙材料是无定形的磷灰石磷酸钙,例如一种稀少结晶的磷灰石磷酸钙。这种稀少结晶的磷灰石磷酸钙可具有类似于天然存在的骨矿物质的钙-磷(Ca∶P)比例,在优选的实施方案中,此Ca∶P比例小于1∶1.50,优选地大约是1∶1.40。骨生成蛋白可以是骨形态发生蛋白(BMP)家族中的一员,包括BMP-2,BPM-4,BMP-5,BMP-6,BMP-7,BMP-10,BMP-12和BMP-13。在优选的实施方案,其骨生成蛋白是BMP-2或BMP-6。泡腾剂可以是选自如下种类的气体:二氧化碳,空气,氮气,氦气,氧气和氩气。在优选的实施方案,其泡腾剂是碳酸氢钠。该碳酸氢钠可以以大约10%-40%(W/W)的浓度存在。这种组合物还可进一步包含如下一种或几种补充材料:例如药剂学允许的盐,多糖,肽,蛋白质,氨基酸,合成的聚合物,天然聚合物和表面活性剂;固体结构例如海绵,网状物,薄膜,纤维,凝胶,细丝,微粒和纳米颗粒;易受生物侵蚀的聚合物例如胶原,糖原,几丁质,纤维素,淀粉,角蛋白,丝,核酸,脱矿物质骨基质,衍生化的透明质酸,聚酐,聚原酸酯,聚乙醇酸,聚乳酸以及它们的共聚物和衍生物;α-羟基羧酸例如聚(L-丙交酯)(PLLA),聚(D,L-丙交酯)(PDLLA),聚乙交酯(PGA),聚(丙交酯-共-乙交酯)(PLGA),聚(D,L-丙交酯-共-三亚甲基碳酸酯),和聚羟基丁酸酯(PHB),以及聚酐,它们共聚物和衍生物;SiO2、Na2O、CaO、P2O5、Al2O3和CaF2;以及多糖、肽和脂肪酸。该组合物还可进一步包含第二种活性作用剂,例如Hedgehog,Frazzled,Chordin,Noggin,Cerberus和Follistatin蛋白。
另一方面,本发明涉及治疗哺乳动物骨缺损的方法,包括对骨缺损部位施加有效剂量的骨生成组合物,其中该骨生成组合物包含骨形态发生蛋白,磷酸钙材料和泡腾剂,在优选的实施方案,其泡腾剂是碳酸氢钠。
还有另一方面,本发明涉及将骨生成蛋白,磷酸钙材料和泡腾剂用于制备传递骨生成蛋白的药剂。
发明详述
本发明的目标是适合用于骨组织修复再生和增长的骨诱导组合物。该组合物包含生物相容性和生物可再吸收的磷酸钙材料,泡腾剂和生物活性作用剂。一旦硬化,这种磷酸钙材料将为新骨生长提供可再吸收的支架。泡腾剂通过促进形成分离的大颗粒而防止磷酸钙形成单一的整体结构,在磷酸钙硬化的过程中这些大颗粒可分散开。生物活性作用剂可刺激增强现存的或者渗入的前体细胞或其它细胞的骨生成活性。这种骨诱导组合物在例如osteopenc骨中具有使骨组织骨质增长和再生的用途,以及在骨断裂时用于组织修复和增强,用于牙齿植入,骨移植和修补等。
在此使用的各词“磷酸钙材料”意指一种含有磷酸钙作为主要成分的合成的骨代用品材料。适合的以磷酸钙为基础的材料是本领域熟知的,包括但不限于无定形磷灰石磷酸钙,羟基磷灰石,磷酸三钙和氟磷灰石。在优选的实施方案,其磷酸钙材料是稀少结晶的磷灰石磷酸钙固体,它具有类似于天然存在的骨矿物质的钙-磷(Ca/P)比例。通过组合作为反应物的无定形磷灰石磷酸钙,促进剂和水性液体,形成可逐渐变硬的糊状物,这样可制备这种材料。在另一实施方案中,是通过结晶磷酸钙反应物的固态酸-碱反应,形成结晶的羟基磷灰石固体来制备磷酸钙材料。
“泡腾剂”指的是一种气体物质,或者是一种可导致气泡形成,起泡沫或释放气体的物质。
在此使用的名词“无定形的”意指具有显著无定形特征的材料。显著的无定形特征预示着具有大于75%无定形含量,更优选地是大于90%无定形含量,并且以宽的无特征峰X-射线衍射图为特征。
“生物活性的”是指在植入物和植入物周围诱导硬组织形成的材料。当在软组织中植入时,其生物活性还可能需要有生长因子或营养因子存在,或者需要种植具有硬组织形成细胞类型的植入物。
在此使用的名词“生物相容的”意指该材料对受植入者不会引发明显的有害反应。经常有这样的情况,当外来物体被导入活体内时,此物体将诱发出免疫反应,例如对宿主有不利影响的炎症反应。例如,虽然一般认为羟基磷灰石是“生物相容的”,但是,当结晶羟基磷灰石微载体被嵌入动物肌肉内,仍然看到有明显的炎症和组织坏死(见例如Ijnterma等,国际药学杂志112:215(1994))。
“可生物再吸收的”指的是材料在体内能够被再吸收。再吸收过程包括通过体液,酶或细胞的作用消除原来植入物材料。例如,再吸收的磷酸钙可以被再沉积作为骨矿物质,或者在体内被再利用,或排泄出。在此使用的名词“高度可生物再吸收的”意指在一年内,肌肉内或皮下植入的材料其总重量的至少80%被再吸收了。在优选的实施方案,该材料将在9个月内,6个月内,3个月内,理想地在1个月内被再吸收。
泡腾剂的“有效用量”是材料变硬过程中足以影响大颗粒形成的泡腾剂用量,并且将取决于所使用的磷酸钙材料。一般来说,泡腾剂的用量是按重量的大约1%-90%加入,优选地是按重量的大约1%-50%,更优选地是按重量的大约10%-40%。
如在此使用的“大颗粒”意指直径在大约100微米-1毫米的颗粒或微粒。本发明的磷酸钙组合物变硬时形成的大颗粒材料是生物相容性的(也就是说,这种大颗粒具有避免引起炎症反应的足够大小),并且如下面所述,是大孔隙的。
在此使用的“大孔隙的”指的是已变硬的磷酸钙材料具有允许细胞迁移和渗入的足够直径的孔隙。在优选的实施方案,按照本发明形成的大孔隙材料具有大于30微米的孔隙直径,更优选地直径在大约30-200微米,而最优选地直径在大约50-100微米。本发明的大孔隙材料有助于细胞迁移和渗入其中,分泌细胞外骨基质,并促进细胞-基质间的相互作用。
生物活性作用剂的“有效剂量”,是足以刺激增强现存或者渗入的前体细胞或其它细胞的骨生成活性的生物活性作用剂用量,该剂量将取决于被治疗缺损的大小和性质,以及所使用磷酸钙材料的组成。一般地,被递送的生物活性作用剂的剂量在大约0.1-100mg的范围内,优选地是大约1-100mg,最优选地是大约10-80mg。
补充材料的“有效用量”是足以使复合材料产生所要求机械或化学特性的补充材料用量。
“硬化”是指使可延展的磷酸钙组合物转化成为坚硬磷酸钙材料的过程。当磷酸钙材料变为基本上不可变形的固体时,则被认为是“硬化了”。这种硬化的磷酸钙材料具有最小的可压缩性,并且有助于承受与弹性变形相反的塑性变形。
在此使用的名词“稀少结晶的磷灰石磷酸钙”,“PCA磷酸钙”和“PCA材料”,都是指一种合成的稀少结晶的磷灰石磷酸钙。这种稀少结晶的磷灰石(PCA)材料不一定局限于单一的磷酸钙物相,只要它具有特征性X-射线衍射(XRD)图形和FTIR图形。PCA磷酸钙基本上具有与骨相同的XRD频谱。通常其频谱特征是在20°-35°的范围内有唯一的二个宽峰,并在26°伴有一个中心峰,在32°伴有另一个中心峰,并且在563cm-1,1034cm-1,1638cm-1和3432cm-1(±2cm-1)有FTIR峰。在603cm-1和875cm-1可见尖锐的肩峰,并在1422cm-1和1457cm-1伴有具最大值的双峰。
在此使用的“水合前体物”是指干燥的PCA前体物在有限量水溶液(即每克前体物粉末加少于大约1ml水溶液)存在下,通过水合作用形成的糊状物或油灰状物。这种水合前体物在不同的组合中,取决于其转化进展的程度,可能既含有反应物又含有产物。在此所述的可注射的和可成形的PCA前体糊状物都是水合前体物。优选的“可注射性”水合前体物具有适合于通过18号皮下注射针头传送的粘稠度。
在此使用的名词“促进剂”,是指促进水合前体物硬化,并可增进无定形磷酸钙(ACP)向PCA磷酸钙转化的作用剂或处理剂。某些促进剂参与转化并被掺入PCA材料中,另一些被称为“被动”促进剂的促进剂不包含在转化过程中。
“活性的”在此用于指当与液体混合形成水合前体物时,在有与此前体物材料硬化有关的促进剂存在下,磷酸钙进行向PCA材料转化的能力。优选的ACPs具有如下特征:能够完全转化,能够快速转化并同时硬化,能够同其它惰性化合物一起进行转化,以及/或者能够转化成基本均一的PCA材料。在使ACP与第二种磷酸钙反应的情况下,其“转化”可以包含ACP和第二种磷酸钙的转化。硬化程度和硬化过程的动力学也是活性的重要因素。某些ACPs比另一些ACPs更具活性。如果存在弱促进剂如磷酸二钙二水合物(DCPD)时,ACP能进行转化和硬化成PCA材料,则认为它是“高度活性的”。优选的高度活性ACP,在37℃,存在弱促进剂DCPD和水的情况下,在小于12小时内可产生硬化的PCA材料,在大约1-5小时内,理想的在10-30分钟内硬化就基本上完成了。
磷酸钙材料
本发明的磷酸钙成分可以是本领域已知的任何一种生物相容的磷酸钙材料。借助于多种方法中的任何一种,使用任何适合的起始成分,都可以产生这种磷酸钙材料。例如,通过组合作为反应物的无定形磷灰石磷酸钙,促进剂,以及水性液体以形成硬化的糊状物,可产生这种磷酸钙材料。按另一种方式,还可通过结晶磷酸钙反应物的固态酸-碱反应形成结晶羟基磷灰石固体来产生此磷酸钙材料,以形成结晶的羟基磷灰石固体。本领域还已知制造磷酸钙基质材料的其它一些方法。
稀少结晶的磷灰石(PCA)磷酸钙
在一个实施方案,其磷酸钙材料是稀少结晶的磷灰石(PCA)磷酸钙,在专利申请U.S.S.N.08/6501704和美国专利No.5,650,176中描述了PCA材料,在此均都整体引入作为参考。此材料还被如下名称的一组专利申请描述:“传递载体”,“使无定形磷酸钙转化形成新颖的生物陶瓷”,“整形外科和牙齿的陶瓷植入物”,以及“生物活性陶瓷组合物”,它们都是在1997年10月16日提出申请,并被变让与ETEX公司(Cambridge,MA),在此被引入作为参考。鉴于这些相关申请中每个都有大量公开内容,对于PCA材料的详细内容在此将不作过多说明,将满足于概述它的特征。
该PCA材料的特征表现为它的生物可再吸收性和它的最少结晶性。它的结晶特性基本上与天然骨相同。PCA材料还是生物相容性的,对受植入者无害。
可以糊状物或油灰状物的形式(即作为水合的前体物)将这种PCA材料植入病人体内。因为本发明可以在体外开始制备均匀的大孔隙磷酸钙材料,并可在室温下缓慢地进行,所以,该材料要在用于手术部位之前“成形”而使不能使用的可能性最小。在生理条件下(即体温和体内压力下)反应明显加速,使材料在适当位置硬化。在手术安装时这种性质特别有用,此时一般要求将定做部件安装在植入位置。例如,含有泡腾剂和生物活性作用剂的PCA糊状物可被使用,并用于填充骨折部位。
按另一种方式,该PCA材料可在体外预先硬化,装入所需要的生物活性作用剂和泡腾剂,晚些时候再被植入。这种方法在不必要定做外形的情况下,以及在要求制备大量植入物的情况下是有用的。
一般情况下,本发明的成形反应是在应用于手术部位之后完成。在生理条件下,该材料一般在少于5小时之内硬化,在大约1-5小时内基本硬化。优选地该材料在大约10-30分钟内基本硬化。该PCA材料的粘度和可成形性,以及其成形反应的速度,都可根据治疗的需要,通过修改几个简单的参数而改变(见例如Lee等的美国专利No.6,027,742,在此被整体引入作为参考)。
通过对干燥的前体物成分混合物加入蒸馏水,形成糊状物或油灰状物形式的浓稠的水合前体物,可启动产生该PCA材料的转化反应。其它的水性试剂如缓冲液,生理盐水,血清或组织培养基,可用于代替蒸馏水。在另一些实施方案中,对前体物粉末加入了足够的水以便形成糊状物,一旦加入本发明的其它成分,这种糊状物容易以18号针头注射。最经常的情况是,所形成的可生物再吸收的磷酸钙材料将是“钙缺乏的”,与对于羟基磷灰石大约1.67的理想化学计量值相比较,它具有小于1.5的钙-磷比例。
通过组合此PCA前体物,以有限量的水水合(以便形成糊状物或油灰状物),并使它硬化成为PAC材料,可以确定合适的PAC材料。理想的前体物在湿润的环境,在体温下或者在体温附近在少于5小时之内能够硬化,而优选地在10-30分钟之内能够硬化。然后可将以这种方式硬化的构件置于试验动物的肌肉内或皮下,并检测生物再吸收性。理想的材料是当植入一个1-5克的小球,在一年内至少80%被再吸收了。优选地是该材料可以被完全再吸收。一般地说,要测定皮下部位材料再吸收的克数比较容易。
在使用至少一种无定形磷酸钙(ACP)前体物的反应中可形成这种PCA材料,优选地是使用活化的或者活性的ACP(见例如PCT专利申请NO WO98/16209,实施例1-4)。在某些情况下,该反应可只使用一种前体物ACP,此ACP以受控的方式部分地或全部转化成PCA材料。还可使用非参与性促进剂以促进活化的ACP转化成PCA材料。无论如何,可以在体外开始、可以以糊状物形态进行、并在37℃显著加速、导致形成硬化磷酸钙产物的反应都是非常优选的。
在水存在时ACP变成PCA材料的转化被促进。ACP一般提供为粉末,并与任何其它的反应物(例如第二种磷酸钙)组合在一起,使它与有限量水相接触,导致形成糊状物或油灰状物。然后,该水合的前体物硬化,并且此硬化过程与PCA材料的形成相关。ACP变成PCA磷酸钙的转化是作为必定会硬化的糊状物或油灰状物以受控的方式进行,在牙科,整形外科或其它治疗应用中具有实用价值。
当无定形磷酸钙被用作产生可再吸收PCA材料的唯一前体物时,重要的是控制ACP转化成高度结晶羟基磷灰石的自然趋势。另一方面,转化的时间进程应该足够快速而具有外科实用价值,一种方法是使含有结晶形成抑制剂的前体物ACP(见例如WO 98/16209,实施例1)与不含结晶形成抑制剂的ACP(如促进剂)组合。可在干燥状态使这些反应物与适当粒度的,并含有过量抑制剂的ACP相混合。然后通过加入水可使反应物水合,随后提高温度(例如,像发生在导入体内之后),使反应物转化成PCA材料。受控转化的其它方法包括使用催化剂。
结晶羟基磷灰石
在第二个实施方案,其磷酸钙材料是结晶羟基磷灰石(HA)。在例如Brown和Chow的美国专利Nos.Re.33,221和Re.33,161中描述了结晶HA,在此二者均被引入作为参考。Brown和Chow的专利公开了制备磷酸钙再矿质化组合物的方法,以及制备基于相同磷酸钙结合物的,精细结晶的非陶瓷,可逐渐再吸收的羟基磷灰石载体材料的方法。Constanty等在美国专利No.5,053,212和5,129,905(二者均被引入作为参考)中描述了一个相类似磷酸钙系统,它由磷酸四钙(TTCP)和磷酸单钙(MCP)或它的单水合物形式(MCPM)组成。在此实施方案,是通过结晶磷酸钙反应物的固态酸-碱反应形成结晶羟磷炭石固体来产生磷酸钙材料。
结晶HA材料(通常被称为碳酸磷灰石)可被制备以致使它们是可流动的,可塑的,并且能够在原位硬化(见Constants的美国专利No.5,962,028)。通过组合湿的和干燥的反应形成基本均匀的混合物,使此混合物适当地成形,并使此混合物硬化,可以制成这种HA材料(通常被称为碳酸气饱和的羟基磷灰石)。按另一种方式,还可以将前体反应混合物施用于手术部位,并使其在原位硬化和/或成形。硬化过程中,该混合物结晶成为固体,并且基本上是整体的磷灰石结构。
这种反应物一般将由如下成分组成:基本上没有非结合水的磷酸源,碱土金属,特别是钙源,任选的结晶核,特别是羟基磷灰石或磷酸钙结晶,碳酸钙,以及生理学允许的润滑剂,例如可能含有多种溶质的水。可将其干成分预先制成混合物,随后在基本上呈现均匀混合的条件下与液体成分组合。
磷酸来源可以是任何一种部分地被中和的磷酸,特别是像在单碱磷酸钙,相当于和包括第一质子完全中和。另外或补充地说,它可以由基本上没有结合水的,可能以结晶形式的正磷酸组成。钙来源通常将包括带相反电荷的离子,如碳酸盐或磷酸盐等,特别是磷酸钙和磷酸盐如磷酸四钙或磷酸三钙的二重来源。
可在加入湿成分之前将各种干成分组合。通过搅拌可组合这些成分,并且搅拌可用于调节各成分之间反应的程度。在开始搅拌之前或者在完成机械搅拌之前,可加入任何一种或全部干成分,在搅拌之后,当仍然是静止状态时使此混合物退火,随后是一段持续静置时间,在此过程中混合物发生硬化。
泡腾剂
本发明提供了一种新颖的方法,用于产生在生理条件下(即施用之后)可“自我形成颗粒”并分散成为硬化的大颗粒或大微粒的磷酸钙基质或支架材料。这种磷酸钙材料可以是本领域熟知的任何生物相容性的磷酸钙材料,例如上述的PCA磷酸钙材料和结晶羟基磷灰石材料。令人吃惊的是,本发明者已发现,对这些磷酸钙材料加入泡腾剂可基本改变这种材料的生物学、化学和机械学性质,从而显著地提高它的治疗实用价值。本发明的泡腾剂可以是在生理温度和/或压力下产生气泡或释放气体的任何药剂学允许的物质。
目前用于产生磷酸钙材料为以种植组合物用途的可利用的所有方法,都存在某些固有的缺点,包括为了以注射器施用,由于在生产或制备过程颗粒形成而导致的有限可注射性。为了避免引起炎症反应,供生物活性物质附着的预先制成的磷酸钙颗粒必须是大颗粒(理想的是100-1000μm)。但是,这种预先制成的大颗粒不容易为满足经皮注射的要求通过小号针头注射。并且,这些颗粒通常难以操作和使用,并且许多都是通过烧结过程产生的,这就使它们基本上不可再吸收。此外,活性作用剂只可以与预先形成的颗粒混合而导致表面包涂,而不是被均衡地包埋或分散在整个材料中。分散便于当基质被再吸收时生物分子更多地受控释放。
本发明的一个重要方面是,在手术安装时容易使用本发明的生物陶瓷材料,这是超越本领域已知的其它骨代用品复合材料的显著改进。具体地说,将泡腾剂加到该组合物的其它成分(例如磷酸钙材料和任何补充材料)中,引起在特定条件(即生理温度和/或压力)下气体发生泡沫或起泡。起泡或发泡引起当体内注射或植入时磷酸钙材料形成颗粒并分散开。当硬化和/或粘结反应进行时,同时出现颗粒形成,并且使活性作用剂(可将它与其它成分混合,或者在临施用之前加到混合物中)均匀地分散在每个颗粒的整个体积中。
加入适量的泡腾剂以防止形成整体的磷酸钙团块。泡腾剂迅速和完全地与广泛多种磷酸钙和其它具有钙或磷的材料反应,提供均匀的可注射性传递载体。取决于特定的磷酸钙材料,选择泡腾剂以便足以干扰其硬化或粘结过程,使之形成比较均匀的颗粒,但是并不达到致使磷酸钙水泥“无活性”的程度。只有在体内注射或植入之后加入泡腾剂才引起发生真正的颗粒形成。因此,在注射或植入之前的磷酸钙材料的制备和/或这种水泥的配制过程中,不发生颗粒形成。泡腾剂存在时形成的颗粒是足够地大颗粒,可防止发炎反应(一般大于30μm),又是足够地小颗粒,可提供优势的表面面积与体积比例。大的表面面积与体积的比例,使之当新骨再生时能够迅速再吸收磷酸钙材料。大的表面面积还有助于生物活性作用剂的释放,另一方面又可在手术部位仍然保留此作用剂持续骨诱导所需要的适当长的时间。此外,大的表面面积与体积的比例还有助于细胞迁移和渗入材料基质中分泌细胞外骨基质,并且提供形成道路。使用本发明的方法和组合物在体内形成的颗粒在1-2000μm的范围内,优选地在30-1000μm的范围内,更优选地在30-500μm的范围内,而最优选地在50-100μm的范围内。
在一个实施方案中,其泡腾剂是一种溶解在水合磷酸钙材料中的气体。可在压力下使该气体溶解于材料中,也就是说,通过使此复合材料经受这种气体加压,但是,它对粘结反应是惰性的。然后当置于生理温度下(即当注射或植入时),由于随着温度增加气体溶度降低,该气体被释放出来。在这些状况下,只是在体内硬化过程中发生气体消散和随后的颗粒形成,并不会发生在施用之前。这点是特别引人注目的,因为不希望在室温下在注射器内发生颗粒形成。仅作为例子的适合气体包括二氧二碳,空气,氮气,氦气,氧气和氩气。
在另一实施方案中,其泡腾剂是一种挥发性液体,在生理温度下它会蒸发。
在还有另一实施方案中,其泡腾剂是一种固体材料,溶解时它会放出气体。例如,碳酸氢钠当它转化为不稳定的碳酸中间产物时会放出二氧化碳气体,中间产物随之变为二氧化碳和水。
生物活性作用剂
任何促进或刺激新骨生长的有效的生物作用剂都可通过本发明的磷酸钙材料传送。特别有意义的是骨诱导物质例如骨形态发生蛋白(例如重组的人BMP-2),脱矿质化的骨基质,转化生长因子(例如TGF-β),以及已知诱导骨形成的其它有机物种类。另一方面或者此外,为了尽量充分地骨化,传递载体可随同骨形成细胞一起被种植。
骨诱导蛋白
生物活性作用剂优选地选自被称为转化生长因子-β(TGF-β)蛋白质超家族的蛋白质家族,它包括激活素(activin),抑制素(mhibin)和骨形态发生蛋白(BMP)。最优选的是,该活性作用剂包括选自一般被称为BMP的蛋白质亚类的至少一种蛋白质,已发现这种蛋白质具有骨生成活性以及其它的生长和分化活性。这些BMPs包括例如在美国专利No.5,108,922;5,013,649;5,116,738;5,106,748;5,187,076;和5,141,905中公开的BMP蛋白BMP-2,BMP-3,BMP-4,BMP-5,BMP-6和BMP-7,在PCT专利公报WO 91/18098中公开的BMP-8,在PCT专利公报WO 93/00432中公开的BMP-9,在PCT专利申请WO 94/26893中公开的BMP-10,在PCT专利申请WO 94/26892中公开的BMP-11,或者在PCT专利申请WO 95/16035中公开的BMP-12或BMP-13,在美国专利5,635,372中公开的BMP-15,或者在美国专利5,965,403中公开的BMP-16。作为活性作用剂在本发明有用的其它TGF-β蛋白包括Vgr-2,(Jones等,分子内分泌学6:1961-1968(1992)),以及任何生长和分化因子(GDFs),包括在如下PCT专利申请中描述的:WO 94/15965,WO 94/15949,WO 95/01801,WO 95/01802,WO 94/21681,WO 94/15966,WO 95/10539,WO 96/01845,WO 96/02559等等。在WO 94/01557中公开的BIP,在JP专利公报号:7-250688中公开的HP00269,以及在PCT专利申请WO 93/16099中公开的MP52也可用于本发明。所有上述专利申请中的公开内容在此被引入作为参考。目前优选地用于本发明的BMP亚群包括BMP-2,BMP-4,BMP-5,BMP-6,BMP-7,BMP-10,BMP-12和BMP-13。最优选的活性作用剂是BMP-2,在美国专利5,013,649中公开了它的序列,它的公开内容在此被引入作为参考。也可以使用本领域已知的其它一些BMPs和TGF-β。
这种活性作用剂可以重新组合产生,或者从蛋白质组合物中纯化得到。该活性作用剂如果是TGF-β如BMP,或者其它的二聚体蛋白质,则可以是同型二聚体,或者可以是带有其它BMP的异型二聚体(如各由一个单体BMP-2和BMP-6组成的异型二聚体),或者是带有TGF-β超家族其它成员如激活素,抑制素和TGF-β1的异型二聚体(如各由一个单体BMP和TGF-β超家族相关成员组成的异型二聚体)。例如,在已公布的PCT专利申请WO 93/09229中描述了这种异型二聚体蛋白的例子,其说明书在此被引入作为参考。
这种活性作用剂可以进一步包含一些补充成分如Hedgehog,Frazzled,Chordin,Noggin,Cerberus和Follistatin蛋白。在如下文献中概述了这些蛋白质家族:Sasai等,细胞79:779-790(1994)(Chordin),PCT专利公报WO 94/05800(Noggin),以及Fukui等发生生物学159:131-139(1993)(Follistatin)。在WO 96/16668,WO 96/17924和WO 95/18856中描述了Hedgehog蛋白。Frazzled蛋白家族是最近发现的蛋白质家族,它与被称为Frizzled的受体蛋白家族的细胞外结合功能区具有高度同源性。Wang等细胞化学杂志271:4468-4476(1996)中描述了这种Frizzled的基因家族和蛋白质家族。该活性作用剂还可以包括其它一些可溶性受体如在PCT专利公报WO95/0798中公开的被截剪的可溶性受体。根据WO 95/07982的论述,本领域的技术人员将可意识到,对于其它许多受体蛋白都可以制备这种被截剪的可溶性受体。这些也应包括在本发明的范围内。上述文献在此均被引入作为参考。
在此活性作用剂的有效用量,是可有效到刺激增加现有的或渗入的前体细胞或其它细胞骨形成活性的用量,并且将取决于待治疗缺损的大小和性质,以及所使用的载体。一般地,将被逆送的蛋白质用量在大约0.1-100mg的范围内,优选地是大约1-100mg,最优选地是大约10-80mg。
骨形成细胞
在一个实施方案,为了最充分地骨化,可将磷酸钙组合物随同骨形成细胞如前体细胞,干细胞和/或成骨细胞一起种植。通过将磷酸钙组合物置于与该病人自身来源的骨形成细胞接触就最容易地达到此目的。可以在骨相关联的组织、血液或流体中找到这些细胞,这种液体包括已经同骨或骨物质或者部位接触的外源性液体,而骨物质或骨部位包括骨膜的松质骨或骨髓。当连同一些部件如螺丝和钉子一起使用时,这些部件导入骨中将伴随有骨膜破裂和/或出血,则不需要作进一步的接种。对于板状材料,它仅对抗皮质骨,诱发将咬合这些部件的骨膜损伤是可取的。在还有其它一些实施方案中,有实用价值的是,通过在植入部位除去部分皮质骨,在骨内手术准备一个安装位置。可将从该病人收集的骨形成细胞导入植入物中以便增加骨化作用。如果在受植入者排斥骨形成细胞之前出现了所要求数量的骨质再生,使用非自体移位骨细胞也属于本发明的范围。因此,在某些实施方案中,从初始来源,细胞系或细胞库得到的细胞和组织都可能是有用的。见Lee等的美国专利No.6,132,463,在此将它引入作为参考。
补充材料
通过将磷酸钙材料,泡腾剂和生物活性作用剂与选用的补充材料组合在一起,可制备本发明的复合材料。磷酸钙可用作加强材料或基质,或者作为二者。该磷酸钙材料在其初始的水合形成一般保持在大约PH6-7,因此与广泛的添加物是相容性的,没有有害作用。补充材料的选用是根据它与磷酸钙和其它成分的可相容性,以及它赋与此组合物一些特性(生物的,化学的或机械的特性)的能力,这些特性是特定的治疗目的所希望的。例如,可选择补充材料以便改善此磷酸钙材料的张力和硬度,增加其抗断裂韧性,提供成形能力,以及/或者改变其流动性和凝固时间。
可以不同的用量和不同的物理形态将补充材料加到磷酸钙组合物中,取决于所预期的治疗用途。例如,这种补充材料可以是固体结构形式,例如海绵、网状物、薄膜、纤维、凝胶、细丝或颗粒状,包括微粒和纳米颗粒。补充材料本身可以是一种组合物,补充材料可以是与可再吸收磷酸钙密切混合的颗粒状或液体添加物或搀入剂。当与PCA磷酸钙材料密切混合时,该补充材料可在肉眼可见的水平干扰其粘结反应。这种情况随着补充材料包涂了一定百分数的水泥微粒,致使被包涂的微粒发生弱粘结反应而出现。另一种情况是,这种液体或固体可引起活性成分之间发生物理学分离,导致水泥成形(或颗粒)的病灶区。这种补充材料对磷酸钙可起基质的作用,磷酸钙被包埋或散布在此基质内。按另一种方式磷酸钙可对补充材料起基质的作用,补充材料被散布在其中。补充材料还可被用作磷酸钙体表的涂料,例如作为装配后涂料,以便延迟再吸收时间,或者影响此生物陶瓷材料的性质。最后,还可用磷酸钙组合物包涂补充材料。
补充材料理想地是生物相容性的,也就是说,当被导入受植入者时该材料不会引起有害的反应,在许多情况下,还希望此补充材料是可生物再吸收的。补充材料对钙,磷酸盐或磷酸钙可以具有亲和力,这将增加磷酸钙/补充材料界面的强度。此亲和力可以是特异性的,或者是通过非特异性离子相互作用中介的。仅作为例子,适合于在此组合物中用作基质的易受生物侵蚀的聚合物包括但不局限于:胶原、糖原、几丁质、纤维素、淀粉、角蛋白、丝、核酸、脱矿质骨基质、衍生化的透明质酸、聚酐、聚原酸酯、聚乙醇酸、聚乳酸、以及它们的共聚物。特别是已知如下聚合物是易受生物侵蚀的并适合用于本发明:αZ-羟基羧酸的聚酯如聚(L-丙交酯)(PLLA),聚(D,L-丙交酯)(PDLLA),聚乙交酯(PGA),聚(丙交酯-共-乙交酯)(PLGA),聚(D,L-丙交酯-共-三亚甲基碳酸酯),和聚羟基丁酸酯(PHB),以及聚酐如聚(酐-共-酰亚胺),以及它们的共聚物。此外,生物活性玻璃组合物如包含SiO2、Na2O,CaO、P2O5、Al2O3和/或CaF2的组合物都可用于同本发明的磷酸钙组合物组合。有用的其它易受生物侵蚀的聚合物可包括多糖,肽和脂肪酸。
易受生物侵蚀的聚合物有益地被用于制备可生物再吸收的硬部件,例如但不限于用于骨植入部位的骨质之间的钉子、销杆、螺丝、板材和锚状物。可生物再吸收的纤维可以须状物形式存在,它按照本领域已知的组合物设计和制造原理与磷酸钙相互作用。通过压制磷酸钙和聚合物的粉末状微粒混合物可使这种硬部件成形。另外,用PLLA纤维可以使磷酸钙基质加强,用于制备可生物降解的自我加强的组合物,使用的PLLA纤维与Tormala等,临床医学材料10:29-34(1992)描述的纤维相似,此文献在此被引入作为参考。
可生物再吸收的聚合物还可被用于制备骨胶质或油灰用在承重部位。可将补充材料加到组合物中以便增加骨胶质的可压缩性和承重性能。特别是可将碳纤维或其它增强纤维加到组合物中。在产生纤维增强的骨代用胶质的过程中,有益的是等离子刻蚀这种纤维以便改善磷酸钙/纤维界面的品质和强度。还可以使磷酸钙在37℃硬化,被制成粉末或者制成碎片,并且同如下已知的材料混合:粘合剂如骨胶质水泥,填充物,灰泥,环氧树脂和其它的磷酸钙;或者凝胶例如但不限于硫酸钙,海藻胶质,胶原或可购买到的产品如Endooone(Merck),Hapset(Lifecore Biomedicd),SRS(Norian),Bonesource(Leibinger),Collografe(Zimmer),Osteograft(CereMed)以及Simplex(Howmedica)。为了应用,在硬化的磷酸钙将被分散在粘合剂物质中的情况下,最通常地是借助于本领域已知的方法制备此粘合剂,并使它以大致相等的体积同磷酸钙微粒混合,尽管实际的比例将以本领域已知的方式改变,以便产生所要求粘稠度,可塑性和粘性的组合物。
在还有另一实施方案中,可用本发明的磷酸钙组合物包涂一般由聚酯制成的编织的缝合材料,以便改善它们的生物相容性。可通过将缝合材料浸入包含磷酸钙材料的水泥浆中来制备包涂的缝合材料,通过对缝合材料和磷酸钙微粒二者之一,或者对二者作表面处理,可改善缝合材料对磷酸钙涂料的亲和性。表面处理包括等离子刻蚀和/或化学结合。
在其它一些实施方案中,提供了一种包含磷酸钙材料和不可再吸收或微少再吸收材料的组合物。适合的不易侵蚀性或少量侵蚀性材料包括右旋糖酐,聚乙烯,聚甲基异丁烯酸酯(PMMA),碳纤维,聚乙烯醇(PVA),聚(乙烯对苯二酸酯),聚酰胺,生物玻璃,以及前面列举的用于骨胶质或油灰的化合物。
另一种用途是将一些有用的物体如栓钉或增强网长期埋入骨本身。这种物对于稳固地附着于天然骨起锚的作用。这在使韧带和腱附着于骨特别有用。可将包含可生物再吸收和骨化的磷酸钙的物体,以及适合的不可再吸收性硬部件置入骨中,并且在骨胶质配制中进一步用添加的磷酸钙材料或复合材料加以保护。因此,在磷酸钙材料再骨化之后,这种硬部件成为被埋置于骨中。
在本发明的还有另一实施方案中,通过将磷酸钙或复合材料与可改变复合材料的再吸收特性、凝固时间和/或流动性的添加物混合,制备了一种组合物。例如,可将硅酮油或其它润滑聚合物或者液体加入到组合物中,以便为了通过注射器对受植入者投递,改善组合物的流动性。优选地,该润滑剂是生物相容性的,并且在磷酸钙组合物在体内凝固之后能够迅速从骨代用品材料组合物中沥滤出。适合的润滑剂,仅作为例子,包括聚合物蜡、脂类和脂肪酸。可以按大约0.1%-30%的重量浓度使用润滑剂。
下面的实施例即将对本发明的优选实施方案作详细说明。可以预料到,对于本领域的技术人员根据这些描述,在其实践中将出现许多修改和变化。相信这些修改和变化将包括在所附的权利要求中。这些实施例无论如何都构成对本发明的限制。
此申请说明书全篇引用的所有参考文献、专利和公布的专利申请的全部内容,在此都被引入作为参考。
具体实施方式
这些实施例中使用的所有成分都是药品纯度等级。磷酸钙成分是作为商品得到的骨代用品材料,由Etex公司(38Sydney Street.Cambridge.MA 02139)以商品名CEREDEX出售的。所用的生物活性作用剂是重组的人骨形态发生蛋白-2(rhBMP-2)。在美国专利No.5,013,649 4详述了BMP-2的制备方法和特性。
实施例1:磷酸钙组合物的制备
如在美国专利No.5,650,176中所述的制备稀少结晶的无定形磷酸钙磷灰石糊状物,不同的是对无定形磷酸钙(ACP)粉末前体物加入了按重量20%碳酸氢钠。然后用有限量水将此ACP水合形成糊状物,在室温下20-30分钟之内此糊状物仍然是可操作的。
实施例2:体外植入分析
如实施例1中所述制备磷酸钙组合物。然后将水合的糊状物注射进入体温下的生理盐水浴中。在模仿的体内条件下(即37℃),此磷酸钙材料硬化成为大颗粒。
实施例3:肌肉内注射
如实施例1中所述制备含有按重量20%碳酸氢钠的第一种磷酸钙组合物。如在美国专利No.5,650,176中所述制备第二种磷酸钙糊状物,不同的是对无定形磷酸钙(ACP)粉末前体物加入了按重量29%聚乙二醇,然后用有限量水将此二种ACP组合物水合形成二种糊状物,在外植入注射几小时之后它们二者都形成大约100-1000微米的大颗粒。此外(资料未显示),注射20μgrhBMP-2之后颗粒形成发生,在整体凝固磷酸钙水泥中,或者在自-形成颗粒的磷酸钙组合物中传递此生物活性作用剂。使用在大颗粒(磷酸钙)组合物中传递的rhBMP-2在21天诱导的骨形成量显著多于对照材料(整体水泥),资料未被显示。并且,使用大颗粒磷酸钙材料传递的rhBMP-2局部保留显著地少于对照材料(即大约30%对75%,资料未被显示),本发明的大颗粒组合物可使骨诱导蛋白较快地释放,由于增加了可供破骨细胞再吸收此基质的表面面积。基质的这种再吸收作用本身又从该磷酸钙材料中释放出可溶性rhBMP-2。
实施例4:骨切开术腓骨内注射
如实施例1中所述制备含有按重量%碳酸氢钠的磷酸钙组合物。将20μg rhBMP-2加入到所形成的ACP组合物中,然后用有限量的水使它水合形成糊状物。将0.5cc这种水合的材料注射进入非人类灵长动物手术骨切开的腓骨中。一天之后出现明显的大颗粒形成和分散。与此相对比,不合碳酸氢钠的标准磷酸钙材料(对照)在注射后1周仍然是整体的固体团块(资料未被显示)。
实施例5:非人类灵长动物腓骨骨切手术
如实施例4中所述制备含有20重量%碳酸氢钠的磷酸钠组合物(rhBMP-2/NaBSM20),此研究的目的是确定在外科手术后7天,对成年雄性Cynomolgus猴一次经皮注射施用rhBMP-2/NaBSM20,对加速腓骨骨切开术伤口愈合的效果。将这些结果同以前的研究相比较,以前是在外科手术后3小时作这种注射(资料未被显示)。在12只动物制造了双侧腓骨骨切开手术,用小的骨髓内栓钉加以固定。在制造骨切开术创伤后7天,对6只动物的一侧骨切开术伤口注射每毫升NaBSM20含有1.5mg rhBMP-2的NaBSM20 0.5mL。留下其对侧腓骨骨切开术伤口不治疗作为手术对照。对其余6只动物的一侧骨切开术伤口注射不合rhBMP-2的缓冲剂/NaBSM20作为载体对照。同样其对侧骨切开术伤口作为不治疗的手术对照。
手术后每隔1周所作的定期放射照相显示出,在rhBMP-2/NaBSM治疗的骨切开术伤口早在注射后1周就有矿质化的骨形成。到注射后2周,放射照相明显可见有相当多的新骨形成。早在治疗后3-5周(骨切开术后4-6周)就存在跨越骨切开术伤口的桥接新骨细胞。到治疗后7周(骨切开术后8周)放射照相显示此骨切开术伤口被愈合。此时已不存在残余NaBSM载体材料的痕迹。在对侧手术对照直到注射后大约3-4周(骨切开术后4-5周)才出现新骨形成的痕迹。在rhBMP-2/NaBSM治疗组治疗后7周(骨切开术后8周),在其对侧手术对照仍然没有桥接细胞或骨切开术伤口愈合的放射照相痕迹。在第二组动物,其缓冲剂/NaBSM治疗的一侧和对侧手术对照的放射照相显示与rhBMP-2/NaBSM治疗组中对侧手术对照相似。在缓冲剂/NaBSM治疗的骨切开手术伤口,在注射后7周(骨切开术后8周)仍然存在残余载体的痕迹。
在骨切开术后8周,rhBMP-2/NaBSM20治疗的骨切开术伤口的抗扭机械强度,显著地大于正常骨的强度和硬度(1.58±0.40对1.24±0.26Nm)。与其对侧手术对照(0.72±0.19Nm),以及与缓冲剂/NaBSM20治疗组和该组的对侧手术骨切开对照(0.87±0.29和0.74±0.21Nm)相比较,rhBMP-2/NaBSM20治疗组的抗扭强度也显著地较大。缓冲剂/NaBSM20治疗的骨切开伤口与来自相同动物对侧手术对照骨切开伤口相比较,以及与rhBMP-2/NaBSM治疗动物的手术对照相比较,它们的抗扭机械强度没有显著的差别。在大约14-16周后未治疗的手术对照骨切开伤口才达到接近正常骨的机械强度。对于骨切开术伤口的硬度地观察到类似的结果。
此研究证明,响应在制造骨切开术伤口后7天注射rhBMP-2/NaBSM20,大于50%地加速了骨切开术伤口的愈合。与在以前的研究中,在骨切开术后3小时和1天以rhBMP-2/NaBSM和rhBMP-2/aBSM治疗的骨切开术伤口中观察到的相比较其新骨形成的出现快得多。与骨切开术后3小时和1天治疗的相比较,在手术后7天治疗的动物其骨切开术伤口抗扭机械强度也比较大。当在3小时和1天这二个时间点给予治疗,骨切开术伤口愈合的加速大约是30-40%,初步结果表明,在制造骨切开术伤口后2周给予治疗也可以达到加速骨切开术伤口愈合的目的。这种研究的结果都表明,在制造这种骨切开术伤口后3小时-7天给予该组合物或rhBMP-2/NaBSM,都可显著地加速骨切开术伤口愈合。
Claims (20)
1.一种用于治疗哺乳动物骨缺损的组合物,它包含作为第一种生物活性作用剂的骨形态发生蛋白,作为载体的磷酸钙材料,以及有效用量的泡腾剂。
2.根据权利要求1的组合物,其中的骨形态发生蛋白选自BMP-2、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9、BMP-10、BMP-12和BMP-13。
3.根据权利要求1的组合物,其中的骨形态发生蛋白是BMP-2或BMP-6。
4.根据权利要求1的组合物,其中的骨形态发生蛋白是两种不同骨形态发生蛋白的异型二聚体。
5.根据权利要求4的组合物,其中的二聚体由BMP-2和BMP-6组成。
6.根据权利要求1的组合物,其中的磷酸钙材料选自无定形磷灰石磷酸钙、羟基磷灰石、磷酸三钙和氟磷灰石。
7.根据权利要求6的组合物,其中的磷酸钙材料是无定形磷灰石磷酸钙。
8.根据权利要求1的组合物,其中的磷酸钙材料是稀少结晶的磷灰石磷酸钙。
9.根据权利要求2-5中任何之一的组合物,其中的泡腾剂是选自二氧化碳、空气、氮气、氦气、氧气和氩气的气体。
10.根据权利要求2-5中任何之一的组合物,其中的泡腾剂是碳酸氢钠。
11.根据权利要求1的组合物,还进一步包含选自固体结构的补充材料,这类固体结构包括海绵,网状物,薄膜,纤维,凝胶,细丝,微粒和纳米颗粒。
12.一种用于治疗哺乳动物骨缺损的组合物,它包含作为第一种生物活性作用剂的骨形态发生蛋白,作为载体的磷酸钙材料,以及有效用量的泡腾剂,其中该泡腾剂是选自二氧化碳、空气、氮气、氦气、氧气和氩气的气体。
13.一种用于治疗哺乳动物骨缺损的组合物,它包含作为第一种生物活性作用剂的骨形态发生蛋白,作为载体的磷酸钙材料,以及有效用量的泡腾剂,其中该泡腾剂是碳酸氢钠。
14.根据权利要求10或13的组合物,其中碳酸氢钠是以10重量%-40重量%的浓度存在。
15.有效用量的权利要求1-8任一项的组合物或权利要求12-14任一项的组合物在制备用于治疗骨缺损的药物中的用途。
16.根据权利要求15的用途,其中泡腾剂是碳酸氢钠并且碳酸氢钠是以10重量%-40重量%的浓度存在。
17.有效用量的含有骨形态发生蛋白、磷酸钙材料和碳酸氢钠的组合物在制备用于治疗骨缺损的药物中的用途。
18.根据权利要求17的用途,其中碳酸氢钠是以10重量%-40重量%的浓度加入的。
19.根据权利要求17或18的用途,其中的骨形态发生蛋白是两种不同骨形态发生蛋白的异型二聚体。
20.根据权利要求19的用途,其中的二聚体由BMP-2和BMP-6组成。
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US5492697A (en) * | 1990-03-05 | 1996-02-20 | Board Of Regents, Univ. Of Texas System | Biodegradable implant for fracture nonunions |
US6077076A (en) * | 1997-12-18 | 2000-06-20 | Comfort Biomedical, Inc. | Bone augmentation for prosthetic implants and the like |
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