CN110139665A - 包含其中骨组织选择性肽与甲状旁腺激素(pth)或其片段结合的融合肽的药物组合物和生物材料 - Google Patents
包含其中骨组织选择性肽与甲状旁腺激素(pth)或其片段结合的融合肽的药物组合物和生物材料 Download PDFInfo
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- CN110139665A CN110139665A CN201780059864.2A CN201780059864A CN110139665A CN 110139665 A CN110139665 A CN 110139665A CN 201780059864 A CN201780059864 A CN 201780059864A CN 110139665 A CN110139665 A CN 110139665A
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- peptide
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- bone tissue
- bone
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Abstract
本发明涉及一种用于预防或治疗骨疾病的包含融合肽的药物组合物,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。更具体地,本发明涉及用于预防或治疗骨疾病的包含融合肽的药物组合物和生物材料,在该融合肽中由SEQ ID NO.3的氨基酸序列表示的一种骨组织选择性肽与由SEQ ID NO.4或5的氨基酸序列表示的甲状旁腺激素(PTH)或其片段结合。该融合肽可以通过选择性地结合骨组织来改善PTH的作用,并且可以通过增加半衰期来降低给药频率。该融合肽可用作治疗骨质疏松症和骨折的皮下或静脉注射型药物组合物,并可与用于组织恢复的医疗器械结合使用以促进骨组织的形成。此外,当该融合肽与牙科和骨科医疗器械的表面结合时,通过改善医疗器械与新骨之间的骨整合,可以改善医疗器械的移植稳定性。
Description
技术领域
本发明涉及一种用于预防或治疗骨疾病的包含其中骨组织选择性肽与甲状旁腺激素(parathyroid hormone,PTH)或其片段结合的融合肽的药物组合物和生物材料。
背景技术
甲状旁腺激素(PTH)是一种由84个氨基酸构成的肽激素,由甲状旁腺分泌。PTH主要作用于肾上腺皮质,是一种与肾上腺皮质结合并增加cAMP、肌醇三磷酸(IP3)和二酰甘油(DAG)生成的生理活性物质。PTH通过增加骨骼和肾脏中钙的吸收来增加血液中的钙浓度。此外,间歇性给予PTH刺激成骨细胞诱导骨形成。
用于骨质疏松症的治疗药物如雌激素、降钙素和二膦酸盐具有抑制骨吸收(骨溶解)的机制,而PTH具有促进骨形成(成骨)的机制。抑制骨吸收的药物不足以增加已患有晚期骨质疏松症的患者的骨量,但是PTH具有直接促进骨生成的机制,因此对患有2型骨质疏松症伴有骨重塑减少或已患有晚期骨质疏松症的患者有益。目前,可从礼来公司(EliLilly and Company)商购的被认为是被批准作为骨质疏松症的治疗药物的产品,该产品使用的是一段由PTH的84个氨基酸中N-末端的34个氨基酸组成的肽。然而,由于的半衰期不超过1小时,故而每天皮下注射给药一次,因此患者依从性较低。此外,使用2年或更久的长时间后,可能会导致副作用,如高钙血症,甚至骨肉瘤的高发病率。因此,禁止使用该产品2年以上。
已经尝试增加PTH的稳定性。例如,PEG(US 6,506,730)或白蛋白(WO 2010/092135)与PTH连接以诱导血液中的长循环,或取代氨基酸以减少酶的降解(KR 10-1183262)。
此外,已经尝试引入生理活性因子来改善牙科和骨科使用的医疗器械的骨再生(骨生成)和骨整合(bone integration或osseointegration)。牙科和骨科使用的医疗器械包括骨移植物、阻隔膜、含胶原的复合材料、金属植入物、螺钉等。然而,由于生理活性因子从表面释放并分解,其效果不足。
因此,作为解决现有技术的上述问题的深入研究的结果,本发明人开发了包含融合肽的药物组合物和生物材料,在该融合肽由骨组织选择性肽与PTH或其片段结合,并且发现含有融合肽的药物组合物对治疗诸如骨质疏松症和骨折等需要骨生成的病况有效,且融合肽结合在牙科和骨科医疗器械的表面,然后移植以增加骨生成的效果,从而完成了本发明。
发明背景部分中公开的信息仅为更好地理解本发明的背景而提供,并不意在包括创建本领域技术人员已知的现有技术的信息。
发明内容
因此,本发明的目的之一是提供一种用于预防或治疗骨疾病的药物组合物,该组合物包含一种具有改善的稳定性、对骨组织的选择性和骨再生(骨生成)效果的融合肽作为活性成分。
本发明的另一个目的是提供一种预防或治疗骨疾病的方法,该方法包括给予包含具有改善的稳定性、对骨组织的选择性和骨再生效果的融合肽作为活性成分的组合物。
本发明的另一个目的是提供包含融合肽作为活性成分的组合物用于预防或治疗骨疾病的用途,该融合肽具有改善的稳定性、对骨组织的选择性和骨再生效果。
本发明的另一个目的是提供一种生物材料,其中具有改善的稳定性、对骨组织的选择性和骨再生效果的融合肽与之结合。
技术方案
为实现上述目的,本发明提供了一种用于预防或治疗骨疾病的药物组合物,该组合物包含融合肽作为活性成分,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
此外,本发明提供预防或治疗骨疾病的方法,其包括给予包含融合肽作为活性成分的组合物,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
此外,本发明提供了包含融合肽作为活性成分的组合物用于预防或治疗骨疾病的用途,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
此外,本发明还提供了一种与融合肽连接的的生物材料,该融合肽中骨组织选择肽与甲状旁腺激素(PTH)或其片段结合。
附图说明
图1图表显示(A)静脉注射时和(B)皮下注射时血液中PTH和其中骨组织选择性肽与PTH结合的融合肽的浓度,其中■代表PTH且●代表其中骨组织选择性肽与PTH结合的融合肽;
图2是骨质疏松症诱导小鼠的股骨的显微CT图像(A),并且显示了骨质疏松症诱导小鼠注射PTH和其中骨组织选择性肽与PTH结合的融合肽后骨矿物质密度(BMD)的测量结果(B),其中■代表无治疗,●代表PTH,▲代表其中骨组织选择性肽与PTH结合的融合肽;
图3是骨质疏松症诱导小鼠注射PTH和其中骨组织选择性肽与PTH结合的融合肽后血液中钙浓度的测量结果,其中■代表无治疗,●代表PTH,▲代表其中骨组织选择性肽与PTH结合的融合肽;
图4显示了将包含PTH和其中骨组织选择性肽与PTH结合的融合肽的骨移植物移植入兔颅骨后新骨的组织学和组织形态学观察结果;
图5显示了在具有荧光标记的PTH和荧光标记的其中骨组织选择性肽与PTH结合的融合肽的植入物附近的骨组织的分布。
具体实施方式
除另有定义外,本发明所使用的所有技术和科学术语的含义与本发明所涉及领域的技术人员所理解的含义相同。一般而言,本文所用术语在本领域内是公知的并且常常使用。
在本发明的一个实施方案中,发现与甲状旁腺激素(PTH)相比,通过给骨质疏松症诱导小鼠注射包含其中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合的融合肽的药物组合物,骨密度增加并且骨生成效果得到改善。
因此,一方面,本发明涉及一种用于预防或治疗骨疾病的药物组合物,其包含融合肽作为活性成分,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
另一方面,本发明涉及一种预防或治疗骨疾病的方法,其包括给予包含融合肽作为活性成分的组合物,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
另一方面,本发明涉及包含融合肽作为活性成分的组合物用于预防或治疗骨疾病的用途,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
根据本发明,该融合肽诱导骨组织的形成。
根据本发明,PTH由SEQ ID NO.4的氨基酸序列表示。
根据本发明,该片段由SEQ ID NO.5的氨基酸序列表示。
SEQ ID NO.4:SVSEIQLMH NLGKHLNSME RVEWLRKKLQ DVHNFVALGA PLAPRDAGSQRPRKKEDNVL VESHEKSLGE ADKADVNVLT KAKSQ
SEQ ID NO.5:SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF
根据本发明,PTH或其片段可以是在大肠杆菌或酵母中表达的重组PTH,或PTH相关肽(PTHrp),或可以通过肽合成生产(Hefti等人,Clinical Science,62,389-396(1982);Liu等人,J.Bone Miner.Res.,6:10,1071-1080(1991);Hock等人,J.Bone.Min.Res.,7:1.65-71(1992))。
根据本发明,骨组织选择性肽由SEQ ID NO.3的氨基酸序列表示。
根据本发明,骨组织选择性肽来源于骨涎蛋白I,但不限于此。
根据本发明,赋予PTH骨组织选择性的肽是对胶原具有结合力的肽,胶原是骨的主要成分。骨组织的结构中矿物质成分沉积在胶原纤维上。因此,骨组织选择性肽促进将PTH迁移到骨组织中。
在本发明的一个实施方案中,从构成细胞外基质的蛋白质中的活性位点的氨基酸序列中分离和提取本文使用的赋予骨组织选择性的肽,并且设计为在提取后通过化学修饰保持活性结构。具体地说,需要该肽包含在人骨涎蛋白I的149到169位置的氨基酸序列YGLRSKS(SEQ ID NO.1)、KKFRRPDIQYPDAT(SEQ ID NO.2)和YGLRSKSKKFRRPDIQYPDAT(SEQID NO.3)中的任一个。为了促进与PTH的化学结合,以CGG-或CGGGGG-间隔子的形式将半胱氨酸添加到选自上面列出的氨基酸序列的氨基酸序列的N端,并进行化学合成来制备该肽。
根据本发明,融合肽可具有如下结构:其中骨组织选择性肽的N末端与PTH或其片段的C末端结合。
骨组织选择性肽可以通过固相肽合成或使用化学交联剂与PTH或其片段的C末端结合,但是本发明不限于此。
根据本发明,化学交联剂可用于将骨组织选择性肽的N末端连接至PTH或其片段的C末端。在这种情况下,可以引入能够与肽末端的半胱氨酸结合的官能团,例如SH基团,或者可以进行处理以形成胺(NH2),从而促进随后使用交联剂进行的交联反应。
化学交联剂可选自:1,4-双-马来酰亚胺基丁烷(BMB)、1,11-双-马来酰亚胺基四乙二醇(BM[PEO]4)、1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(EDC)、琥珀酰亚胺基-4-[N-马来酰亚胺甲基环己烷-1-羧基-[6-酰胺基己酸酯]](SMCC)及其磺酸盐(磺基-SMCC)、琥珀酰亚胺基6-[3-(2-吡啶基二硫代)-丙酰胺基]己酸酯](SPDP)及其磺酸盐(磺基-SPDP)、间-马来酰亚胺基苯甲酰基-N-羟基琥珀酰亚胺酯(MBS)及其磺酸盐(磺基-MBS)、琥珀酰亚胺基[4-(对-马来酰亚胺基苯基)丁酸酯](SMPB)及其磺酸盐(磺基-SMPB),但本发明不限于此。
为了在PTH与骨组织选择性肽结合后除去交联剂,将其中骨组织选择性肽与PTH结合的融合肽进行纯化(如超滤),使得其中骨组织选择性肽与PTH结合的融合肽纯度为90%或更多,优选98%或更多。
在本发明中,该骨疾病选自:骨质疏松症、成骨不全症、高钙血症、骨软化症、佩吉特病、骨质流失和由癌症引起的骨坏死、骨关节炎、类风湿性关节炎、牙周病和骨折,但不限于此。
在本发明中,用于预防或治疗骨疾病的药物组合物可以被配制用于静脉内、腹膜内、肌肉内、动脉内、口服、牙周、心内、髓内、鞘内、经皮、肠内、皮下、舌下或局部给药,但不限于此。
在本发明中,用于预防或治疗骨疾病的药物组合物被配制成选自下组的任何一种,该组由以下组成:注射剂、口腔粘膜剂、胶囊剂、薄膜、贴剂、经皮剂和凝胶,但不限于此。该药物组合物可以通过局部、皮下、静脉内或肠胃外途径给药。通常,根据本发明,该药物组合物可含有治疗有效量的融合肽作为活性成分,在该融合肽中骨组织选择性肽与PTH或其片段结合。
在本发明中,可使用药学上可接受的惰性无机或有机赋形剂通过众所周知的方法制备药物组合物。用于制备注射剂的赋形剂的例子包括但不限于水、乙醇、甘油、多元醇、植物油等。可替代地,注射剂可与防腐剂、镇痛剂、增溶剂和稳定剂组合使用。局部制剂可以凝胶或薄膜的形式制备,并且该凝胶的主要成分优选为胶原、壳聚糖、透明质酸、海藻酸、丙二醇、藻酸丙二醇酯、泊洛沙姆、硫酸软骨素等。
在本发明中,药物组合物中融合肽的含量可以是10至100μg。该药物组合物可以被配制成含有10至100μg剂量的融合肽的单次皮下或静脉注射剂,在该融合肽中骨组织选择性肽与PTH或其片段结合。
在本发明的一个实施方案中,骨再生的效果可以使用与融合肽连接的骨植入物来鉴定,在该融合肽中骨组织选择性肽与PTH或其片段结合。
另一方面,本发明涉及一种与融合肽连接的生物材料,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
根据本发明,该融合肽诱导骨组织的形成。
根据本发明,PTH由SEQ ID NO.4的氨基酸序列表示。
根据本发明,该片段由SEQ ID NO.5的氨基酸序列表示。
根据本发明,骨组织选择性肽由SEQ ID NO.3的氨基酸序列表示。
根据本发明,骨组织选择性肽具有如下结构:其中骨组织选择性肽的N末端与PTH或其片段的C末端结合。
骨组织选择性肽可以通过交联剂与PTH或其片段的C末端结合。交联剂可选自:1,4-双-马来酰亚胺基丁烷(BMB)、1,11-双-马来酰亚胺基四乙二醇(BM[PEO]4)、1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(EDC)、琥珀酰亚胺基-4-[N-马来酰亚胺甲基环己烷-1-羧基-[6-酰胺基己酸酯]](SMCC)及其磺酸盐(磺基-SMCC)、琥珀酰亚胺基6-[3-(2-吡啶基二硫代)-丙酰胺基]己酸酯](SPDP)及其磺酸盐(磺基-SPDP)、间-马来酰亚胺基苯甲酰基-N-羟基琥珀酰亚胺酯(MBS)及其磺酸盐(磺基-MBS)、琥珀酰亚胺基[4-(对-马来酰亚胺基苯基)丁酸酯](SMPB)及其磺酸盐(磺基-SMPB),但本发明不限于此。
根据本发明,该生物材料可以是选自下组的任何一种,该组由以下组成:骨移植物、阻隔膜、植入物和聚合物支架。该生物材料可包括所有种类和类型的骨移植物、阻隔膜、植入物和聚合物支架。
骨移植物包括作为主要成分的衍生自自体骨、牛骨和猪骨的生物体衍生的骨矿物粉末及其多孔块、合成羟基磷灰石粉末及其多孔块、磷酸三钙粉末及其多孔块、或羟基磷灰石和磷酸三钙粉末的混合物及其多孔块。
阻隔膜优选由胶原、壳聚糖、明胶、聚丙交酯、聚丙交酯乙交酯或聚己内酯生产,但不限于此。
植入物可以由钛合金、氧化钛或氧化锆生产,但本发明不限于此。植入物可包括牙科和骨科植入物。骨科植入物包括骨科固定板、骨科骨螺钉、骨科骨钉等。
在本发明中,相对于该生物材料的单位重量(1g),融合肽可以以1至10mg的量存在。更优选地,相对于生物材料的单位重量(1g),融合肽以2至8mg的量存在。
实施例
在下文中,将参考实施例更详细地说明本发明。然而,对于本领域技术人员来说显而易见的是,这些实施例仅用于说明本发明,不应解释为限制本发明的范围。
制备实施例1:通过固相肽合成制备其中骨组织选择性肽与PTH结合的融合
肽
通过使用F-moc固相化学合成,从N末端依次连接骨组织选择性肽(SEQ ID NO.3)和PTH片段(SEQ ID NO.5)来合成该融合肽。将合成的肽序列从树脂上切下,洗涤、冻干,然后通过液相色谱分离和纯化。通过MALDI-TOF试验鉴定纯化的肽的分子量。
比较实施例1:制备PTH片段
通过连接PTH片段(SEQ ID NO.5)使用F-moc固相化学合成来合成肽。将合成的肽序列从树脂上切下,洗涤、冻干,然后通过液相色谱分离和纯化。通过MALDI-TOF试验鉴定纯化的肽的分子量。
制备实施例2:通过交联反应制备其中骨组织选择性肽与PTH结合的融合肽
将1mg PTH片段(SEQ ID NO.5)溶于1ml缀合反应缓冲液(100mM磷酸钠,150mM氯化钠,0.02%叠氮化钠,1mM EDTA)中。将40μl磺基-SMCC(Thermo Scientific,4.8mg/ml)溶液分批少量加入到PTH中,并在室温下避光反应1或2小时。通过截留分子量为500kDa的膜超滤除去未反应的磺基-SMCC。向其中添加SEQ ID NO.3的肽在缀合缓冲液中的溶液(1mg/ml),并且在避光的情况下使所得混合物反应4至8小时。将包含其中骨组织选择性肽与PTH结合的融合肽通过截留分子量为3,000kDa的膜进行超滤,以除去未反应的SEQ ID NO.3的肽。使用MALDI-TOF和SDS-PAGE,鉴定了其中骨组织选择性肽与PTH结合的融合肽的分子量。当考虑到PTH片段的分子量为4,117.8kDa,骨组织选择性肽的分子量为2,365kDa,并且磺基-SMCC增加的分子量为219.09kDa的事实时,理论分子量应为至少6,701.89kDa。
制备实施例3:制备包含其中骨组织选择性肽与PTH结合的融合肽的药物组合物
一种包含融合肽作为活性成分的药物组合物,在该融合肽中骨组织选择性肽与制备实施例2的PTH结合(表1)。
表1
制备实施例3的药物组合物
成分 | 重量(mg) |
其中骨组织选择性肽与PTH结合的融合肽 | 1 |
氯化钠,USP | 8.18 |
琥珀酸钠 | 1.62 |
WFI | 987.5 |
氢氧化钠,NF和/或乙酸,NF | |
总计 | 1g,pH 6 |
比较实施例2:制备包含PTH的药物组合物
制备包含比较实施例1的PTH作为活性成分的药物组合物(表2)。
表2
比较实施例2的药物组合物
制备实施例4:与融合肽连接的骨移植物的制备,在该融合肽中骨组织选择性肽与PTH结合
将1g牛骨衍生的骨移植物置于溶解在己烷中的3-氨基丙基乙氧基硅烷(APTES,1%)中,然后用己烷洗涤三次。结果,在表面上形成胺残基,并向其中加入BMB作为交联剂。将1g与交联剂结合的骨移植颗粒与20mg的其中骨组织选择性肽与制备实施例2的PTH结合的融合肽反应12小时,用甲醇洗涤3次,然后用纯化水洗涤10次,得到固定有其中骨组织选择性肽与PTH结合的融合肽的骨移植物。
比较实施例3:制备包含与其连接的PTH的骨移植物
将1g牛骨衍生的骨移植物置于溶解在己烷中的3-氨基丙基乙氧基硅烷(APTES,1%)中,然后用己烷洗涤三次。结果,在表面上形成胺残基,并向其中加入BMB作为交联剂。将1g与交联剂结合的骨移植颗粒与20mg的比较实施例1的PTH反应12小时,用甲醇洗涤3次,然后用纯化水洗涤10次,得到固定PTH的骨移植物。
制备实施例5:制备其中骨组织选择性肽与PTH结合的融合肽的凝胶型组合物
将20mg的其中骨组织选择性肽与制备实施例2的PTH结合的融合肽与1ml 2%胶原溶液均匀混合,并将所得混合物填充到注射器中。
比较实施例4:PTH的凝胶型组合物的制备
将比较实施例1的20mg PTH与1ml的1%至3%胶原溶液均匀混合,并将所得混合物填充到注射器中。
实施例1:用于测定其中骨组织选择性肽与PTH结合的融合肽的半衰期的测试
将包含比较实施例2的PTH的组合物和包含其中骨组织选择性肽与制备实施例3的PTH结合的融合肽的组合物以100μg/kg的浓度皮下給予SD(Sprague-Dawley)雄性大鼠(体重300-350g),并在0、2、5、10、20、30、60、180、360、720和1,440分钟时收集血液。另外,将组合物以100μg/kg的浓度注射到颈静脉中,在0、5、10、15、30、60、90、120、180和360分钟时收集血液,并且通过以14,000rpm离心10分钟分离血浆。通过酶联免疫吸附试验(ELISA)(Immutopics公司,圣克莱门特,加利福尼亚州)测量PTH的浓度。
图1显示血液中其中骨组织选择性肽与PTH结合的融合肽的随时间浓度。当皮下注射时,在360分钟后未检测到PTH,但在多达1,440分钟时检测到其中骨组织选择性肽与PTH结合的融合肽。在静脉注射的情况下,在180分钟后未测量到PTH,但在多达360分钟时检测到其中骨组织选择性肽与PTH结合的融合肽。这意味着其中骨组织选择性肽与PTH结合的融合肽的半衰期长于PTH的半衰期。
实施例2:其中骨组织选择性肽与PTH结合的融合肽在骨质疏松症动物中的功效测试
使用10mg/kg甲苯噻嗪(拜耳公司(Bayer),韩国)和100mg/kg氯胺酮(柳韩有限公司(Yuhan Co.,Ltd.),韩国)的混合物通过肌内注射麻醉6周龄ICR小鼠,然后小心地完全取出双侧肾脏下方的卵巢。通过常规方法进行缝合,肌内注射3mg/kg的庆大霉素(JW制药公司(JW Pharmaceutical Corporation),韩国)。
卵巢切除术后3个月,检查是否发生骨质流失。将包含比较实施例2的PTH的药物组合物以每天20μg/kg给予3个月,并且将包含其中骨组织选择性肽与制备实施例3的PTH结合的融合肽的药物组合物以每周80μg/kg给予6个月。与未治疗骨质疏松症的组相比,评估骨密度的变化。
图2显示了骨质疏松症诱导小鼠注射其中骨组织选择性肽与PTH结合的融合肽后股骨的显微CT图像和骨矿物质密度(BMD)的测量结果。在卵巢切除术后未治疗组中,由于明显的骨质流失,骨密度降低。与用PTH治疗的组相比,用其中骨组织选择性肽与PTH结合的融合肽治疗的组显示骨密度增加(图2(A))。作为BMD(骨矿物质密度)的变化的测量结果,即股骨头中总矿物质含量(图2(B)),发现卵巢切除术后未治疗组中BMD降低。用PTH治疗的组在长达一个月时显示出BMD的增加,并且在两个月开始减少。其中骨组织选择性肽与PTH结合的融合肽显示在多达6个月时BMD增加。这意味着其中骨组织选择性肽与PTH结合的融合肽在骨再生上比PTH更有效。
图3显示了注射其中骨组织选择性肽与PTH结合的融合肽后骨质疏松症诱导小鼠血液中钙浓度的测量结果。使用QuantiChromTM钙测定试剂盒(生物测定系统公司(BioassaySystems),海沃德,加利福尼亚州)测定血液中钙的浓度。在一个月时PTH增加了钙的浓度,但是其中骨组织选择性肽与PTH结合的融合肽没有增加血液中钙的浓度。PTH对人体的影响之一是通过影响骨骼和肾脏来增加血液中钙的浓度。因此,长期给予PTH会引起诱导高钙血症的副作用。然而,证实了其中骨组织选择性肽与PTH结合的融合肽没有增加血液中钙浓度的作用,因为它仅影响骨组织,而不影响肾脏。
实施例3:其中骨组织选择性肽与PTH结合的融合肽的骨再生测试
在麻醉的兔(新西兰白兔,家兔(cuniculus))的颅骨区域中形成直径为10mm的圆形骨缺损部位,并将制备实施例4和比较实施例3中制备的100mg骨移植物移植到骨缺损部位。骨膜和皮肤双重缝合。移植后3周处死动物,将收集的样本固定在福尔马林溶液中,并将组织包埋以产生厚度为20μm的样品。将制备的样品用苏木精-伊红染色以制备未脱钙的样本。用光学显微镜观察制备的样本并成像。
图4显示了将包含其中骨组织选择性肽与PTH结合的融合肽的骨移植物移植入兔颅骨后新骨的组织学和组织形态学观察结果。其中骨组织选择性肽与PTH结合的融合肽的骨再生效果比PTH增加更多。因此,预期在骨再生方面,具有与其中骨组织选择性肽与PTH结合的融合肽结合的表面的骨移植物比与PTH结合的骨移植物更有效。
实施例4:PTH和其中骨组织选择性肽与PTH结合的融合肽的骨迁移测试
将花菁5.5与其中骨组织选择性肽与制备实施例2的PTH结合的融合肽结合,去除未反应的花菁5.5。通过根据制备实施例5的方法制备花菁5.5标记的其中骨组织选择性肽与PTH结合的融合肽。将比较实施例1的PTH与花菁5.5结合,除去未反应的花菁5.5。作为对照组,根据比较实施例4的方法制备花菁5.5标记的PTH。
在比格犬拔牙后8周植入植入物,将100μL的包含花菁5.5标记的其中骨组织选择性肽与PTH结合的融合肽的胶原凝胶注射到手术部位并缝合。移植后3周处死动物,将收集的样本固定在福尔马林溶液中,并将组织包埋以产生厚度为20μm的样品。将制备的样本用苏木精-伊红染色以制备未脱钙的样品。用共聚焦显微镜观察制备的样本并成像。测量植入物附近每个预定单位面积的荧光强度。
图5显示了在具有荧光标记的其中骨组织选择性肽与PTH结合的融合肽的植入物附近的骨组织的分布。当移植PTH时,周围骨组织几乎没有荧光。然而,在其中骨组织选择性肽与PTH结合的融合肽的情况下,观察到分布在周围骨组织中的荧光。这表明与PTH相比,其中骨组织选择性肽与PTH结合的融合肽选择性地结合骨组织。
工业实用性
根据本发明,通过将对骨组织具有选择性的肽引入PTH或其片段,可以增加对骨组织的选择性并增加骨再生效果。此外,通过延长PTH的半衰期,并因此增加给药间隔,可以将肽开发成用于预防或治疗骨疾病的药物组合物,其可以改善患者的依从性。此外,本发明可通过将与骨组织选择性肽结合的PTH用于牙科和骨科的生物材料来进一步改善骨再生效果。
尽管已经详细描述了本发明的具体配置,但本领域技术人员应理解,为了说明目的,本说明书是作为优选实施例提供的,并不应被解释为限制本发明的范围。因此,本发明的实质范围由所附权利要求书及其等效方案限定。
文本文件
参见所附的序列表。
SEQUENCE LISTING
<110> 纳米智能生物医学工程有限公司
首尔大学校产学协力团
<120> 包含其中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合的融合肽的药物组合物和生物材料
<130> PF-B2136
<140> PCT/KR2017/013749
<141> 2017-11-29
<150> KR 10-2017-0126876
<151> 2017-09-29
<160> 5
<170> PatentIn版本3.5
<210> 1
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 骨涎蛋白I
<400> 1
Tyr Gly Leu Arg Ser Lys Ser
1 5
<210> 2
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 骨涎蛋白I
<400> 2
Lys Lys Phe Arg Arg Pro Asp Ile Gln Tyr Pro Asp Ala Thr
1 5 10
<210> 3
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 骨涎蛋白I
<400> 3
Tyr Gly Leu Arg Ser Lys Ser Lys Lys Phe Arg Arg Pro Asp Ile Gln
1 5 10 15
Tyr Pro Asp Ala Thr
20
<210> 4
<211> 84
<212> PRT
<213> 人工序列
<220>
<223> PTH
<400> 4
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn
1 5 10 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser
35 40 45
Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu
50 55 60
Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys
65 70 75 80
Ala Lys Ser Gln
<210> 5
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> PTH
<400> 5
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn
1 5 10 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Phe
Claims (22)
1.一种用于预防或治疗骨疾病的药物组合物,该药物组合物包含一种融合肽作为活性成分,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
2.根据权利要求1的药物组合物,其中该融合肽诱导骨组织的形成。
3.根据权利要求1的药物组合物,其中该甲状旁腺激素(PTH)由SEQ ID NO.4的氨基酸序列表示。
4.根据权利要求1的药物组合物,其中该片段由SEQ ID NO.5的氨基酸序列表示。
5.根据权利要求1的药物组合物,其中该骨组织选择性肽由SEQ ID NO.3的氨基酸序列表示。
6.根据权利要求1的药物组合物,其中该骨组织选择性肽来源于骨涎蛋白I。
7.根据权利要求1的药物组合物,其中该融合肽具有如下结构:该骨组织选择性肽的N-末端与甲状旁腺激素(PTH)或其片段的C-末端结合。
8.根据权利要求1的药物组合物,其中该骨疾病选自:骨质疏松症、成骨不全症、高钙血症、骨软化症、佩吉特病、骨质流失和由癌症引起的骨坏死、骨关节炎、类风湿性关节炎、牙周病和骨折。
9.根据权利要求1的药物组合物,其中该药物组合物被配制用于静脉内、腹膜内、肌肉内、动脉内、口服、牙周、心内、髓内、鞘内、经皮、肠内、皮下、舌下或局部给药。
10.根据权利要求1的药物组合物,其中将该药物组合物被配制成选自下组的任何一种,该组由以下组成:注射剂、口腔粘膜剂、胶囊剂、薄膜、贴剂、经皮剂和凝胶。
11.根据权利要求1的药物组合物,其中该药物组合物中融合肽的含量为10至100μg。
12.一种与融合肽连接的生物材料,在该融合肽中骨组织选择性肽与甲状旁腺激素(PTH)或其片段结合。
13.根据权利要求12的生物材料,其中该融合肽诱导骨组织的形成。
14.根据权利要求12的生物材料,其中该甲状旁腺激素(PTH)由SEQ ID NO.4的氨基酸序列表示。
15.根据权利要求12的生物材料,其中该片段由SEQ ID NO.5的氨基酸序列表示。
16.根据权利要求12的生物材料,其中该骨组织选择性肽由SEQ ID NO.3的氨基酸序列表示。
17.根据权利要求12的生物材料,其中该融合肽具有如下结构,其中该骨组织选择性肽的N-末端与甲状旁腺素素(PTH)或其片段的C-末端结合。
18.根据权利要求12的生物材料,其中该生物材料为选自以下的任何一种:骨移植物、阻隔膜、植入物和聚合物支架。
19.根据权利要求18的生物材料,其中该骨移植物包含作为主要成分的有机体源性骨矿物粉末及其多孔块、合成羟基磷灰石粉末及其多孔块、磷酸三钙粉末及其多孔块、或羟基磷灰石与磷酸三钙粉末的混合物及其多孔块。
20.根据权利要求18的生物材料,其中该阻隔膜由选自下组的任何一种生产,该组由以下组成:胶原、壳聚糖、明胶、聚丙交酯、聚丙交酯乙交酯和聚己内酯。
21.根据权利要求18的生物材料,其中该植入物由选自下组的任何一种生产,该组由以下组成:钛合金、氧化钛和氧化锆。
22.根据权利要求12的生物材料,其中相对于该生物材料的单位重量(1g),该融合肽以1至10mg的量存在。
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KR1020170126876A KR101964376B1 (ko) | 2017-09-29 | 2017-09-29 | 부갑상선호르몬(parathyroid hormone, PTH)에 골조직 선택성 펩타이드가 결합되어 있는 융합 펩타이드를 포함하는 약학 조성물 및 생체재료 |
PCT/KR2017/013749 WO2019066140A1 (ko) | 2017-09-29 | 2017-11-29 | 부갑상선호르몬(parathyroid hormone, PTH)에 골조직 선택성 펩타이드가 결합되어 있는 융합 펩타이드를 포함하는 약학 조성물 및 생체재료 |
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KR20210110070A (ko) | 2020-02-28 | 2021-09-07 | 의료법인 성광의료재단 | 줄기세포를 포함하고 골형성 제제와 병용하는 복합치료 및 그의 용도 |
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