CN113784726A - 非细胞根管填料以及非细胞牙体组织再生促进试剂盒 - Google Patents
非细胞根管填料以及非细胞牙体组织再生促进试剂盒 Download PDFInfo
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Abstract
本发明提供一种非细胞根管填料,其包含四氢异喹啉化合物或其在药学上可接受的盐或者它们的溶剂化物。本发明还提供一种牙体组织再生促进试剂盒,其包含含有丝氨酸蛋白酶的预处理剂以及所述非细胞根管填料。
Description
技术领域
本发明涉及一种能够促进牙髓、牙本质以及根尖牙周组织再生的、不使用干细胞或干细胞成分的非细胞根管填料以及非细胞牙体组织再生促进试剂盒。
背景技术
在超高龄社会中,健康的牙齿和良好的咀嚼能力对于健康长寿至关重要。然而,超过20%的中高龄人会患有一种疾病(感染根管),在该疾病中,已去除牙齿的神经(拔髓)在几十年后再次感染并在牙根下充满脓液。其中约25%的病例即使经过治疗也难以完全治愈。这种慢性感染性病变会对免疫系统受损的高龄人的全身系统造成很严重的影响。许多正在服用骨质疏松治疗药物的高龄人不应拔牙的情况很多。并且,即使拔牙也能够使用种植体的病例数量在中高龄人中减少。
同时,牙齿缺失会导致咬合、发音、味觉、触觉或美观性降低,抑或QOL(生活质量)降低。最近,担心牙齿或口腔功能衰退引起的口腔虚弱可能造成肌肉萎缩,如肌肉力量不足或身体功能低下或者因营养不良等而导致的功能衰退,最终导致中高龄人需要护理。
因此,为了维护牙齿以及口腔功能,已经开发了一种牙髓再生治疗法,其涉及自体牙髓干细胞移植(从无用的自体牙齿中分离出来)或同种异体移植(从他人无用的牙齿中分离出来的牙髓干细胞),以使牙齿恢复至其原始状态,而不会导致拔髓之后的根管感染和拔除牙齿(专利文献1至3)。通过自体或同种异体移植牙髓干细胞可使牙髓再生,不仅如此,通过自体或同种异体移植来源于骨髓或脂肪的其他组织的干细胞也可使牙髓再生,但与牙髓干细胞移植相比,这种组织干细胞移植在牙髓再生量、血管新生量(新生血管形成量)和神经再生量方面较差(专利文献4)。临床研究已经证实通过自体牙髓干细胞移植进行的牙髓再生治疗是安全的,表明其是有效的(非专利文献1)。
牙髓再生治疗包括了如上所述的stem cell therapy(干细胞治疗:干细胞移植法)以及cell homing(细胞归巢:细胞迁移法)。对于具有未成熟牙根的幼龄人的牙齿,通常采用不使用牙髓干细胞,而在根管中填充血块的方法(非专利文献2)。替代方法涉及注射PRP(富血小板血浆)而非血块(非专利文献3)。但是,据说几乎没有观察到牙髓固有组织的再生,主要不过是再生了富含血管的纤维性·骨样组织(非专利文献4)。动物实验中,已经开发了细胞归巢方法,其涉及使用细胞生长因子或细胞因子如基质细胞衍生因子(SDF1)、碱性成纤维细胞生长因子(bFGF)、血小板源性生长因子(PDGF)、干细胞因子(SCF)以及粒细胞集落刺激因子(G-CSF)作为趋化因子而不使用干细胞(非专利文献5)。然而,据报道,这种方法不能再生足量的牙髓,并且大部分是再生具有血管的相对致密的纤维结缔组织,而整个根管还可能被钙化(非专利文献6和7)。因此,迄今为止,干细胞对于牙髓组织再生是至关重要的,特别是在根发育完全的牙齿中(非专利文献8)。
然而,自体干细胞移植的缺点在于:使用牙髓干细胞需要无用的自体牙(如智齿);确认加工细胞制品的安全性是昂贵的;细胞在需要时不能立即供应;以及,在中高龄人中干细胞的特性发生了变化,导致可分离的牙髓干细胞总数减少,培养耗时较长。然而,在同种异体移植中,由于每批次细胞产品数量的增加,细胞生产和加工后的安全性确认的成本较自体移植低,但仍存在尚未解决的问题,诸如确保安全性的牙齿来源问题、当人类牙髓干细胞商品化时牙齿供体的权利和报酬等法律问题以及人体免疫反应的安全性问题。
因此,期望开发一种在不使用干细胞或干细胞来源成分的情况下促进牙体组织(即,牙髓、牙本质以及根尖部牙周组织)在拔髓或感染根管治疗后的再生技术。另外,对促进宿主细胞迁移的干细胞来源的进一步研究表明,可选择适当的信号因子用于牙髓再生。更具体地说,期望在将来开发使用适当的信号因子的牙髓再生方法,该信号因子促进具有血管生成能力和神经分化能力的宿主干细胞的迁移,并抑制具有骨形成和牙骨质形成能力的细胞的迁移(非专利文献9)。
尤其是,与幼龄个体相比,中高龄个体的牙髓再生更延迟。最近,通过使用犬类动物实验确认:在中高龄个体牙髓干细胞移植的牙髓再生治疗过程中,通过将抗CCL11中和抗体/CCR3拮抗剂或ALK5抑制剂与牙髓干细胞一起进行移植可促进牙髓再生。另外,在牙髓干细胞移植之前,通过用胰蛋白酶预处理中高龄个体的牙根管促进了牙髓再生(专利文献5)。所述抗CCL11中和抗体或CCR3拮抗剂抑制CCL11与CCR3的结合,从而阻断信号传导。生长分化因子11(GDF11)与转化生长因子(TGF-)超家族受体ACVR1B(又称ALK4)、TGFBR1(又称ALK5)和ACVR1C(又称ALK7)结合,并通过ALK4和ALK5传递信号。ALK5抑制剂阻断了GDF11信号传导。其认为在牙髓再生时,积聚在牙本质中的牙髓干细胞分泌因子从牙本质中游离出来,促进牙髓再生(非专利文献10)。在含有老化牙髓干细胞分泌因子的体外培养上清液中加入CCR3拮抗剂,显著提高了培养上清液的神经突起伸长的促进作用以及迁移的促进作用。ALK5抑制剂的加入显著提高了培养上清液的血管生成诱导能力及其神经突起伸长促进作用。这些结果表明,CCR3拮抗剂或ALK5抑制剂对中高龄犬牙髓再生的促进作用是基于血管诱导、神经突起伸长和迁移促进作用。然而,未发现使用CCR3拮抗剂或ALK5抑制剂移植牙髓干细胞对于幼龄犬牙髓再生有效(专利文献5)。
胰蛋白酶用作药物(其用于分解坏死组织、血块或变性蛋白质),从而使创面正常以促进抗生素的作用(非专利文献11)。在经胰蛋白酶体外处理的牙本质表面上接种牙髓干细胞增加了细胞的粘附性,并显示出向牙本质细胞的分化增强。研究表明,胰蛋白酶预处理对中高龄犬牙髓再生的促进作用是通过使中高龄牙本质中积累的抑制因子失活或通过前体细胞裂解激活分化促进因子、增加细胞对牙本质的粘附、促进牙髓干细胞向牙本质细胞的分化所引起的。然而,未发现胰蛋白酶预处理对促进幼犬牙髓再生有效(专利文献5)。在未移植牙髓干细胞的单独胰蛋白酶预处理中、或者仅使用CCR3拮抗剂或ALK5抑制剂而未移植牙髓干细胞的处理中,很少观察到牙髓再生(专利文献5)。
引文列表
专利文献
专利文献1:日本特许第5621105号公报
专利文献2:日本特许第6031658号公报
专利文献3:日本特许第5748194号公报
专利文献4:日本特许第5939559号公报
专利文献5:国际公开第2017/170996号
非专利文献
非专利文献1:Nakashima M.,Iohara K.,Murakami M.,Nakamura H.,Sato Y.,Ariji Y.,Matsushita K.:Pulp regeneration by transplantation of dental pulpstem cells in pulpitis:A pilot clinical study.Stem Cell Res Therapy.8(1):61,2017
非专利文献2:Galler KM.:Clinical procedures for revitalization:currentknowledge and considerations.Int Endod J.2016Oct;49(10):926-36
非专利文献3:Kontakiotis EG,Filippatos CG,Tzanetakis GN,Agrafioti A.:Regenerative endodontic therapy:a data analysis of clinical protocols.JEndod。41(2):146-54.2015
非专利文献4:Del Fabbro M,Lolato A,Bucchi C,Taschieri S,Weinstein RL.:Autologous platelet concentrates for pulp and dentin regeneration:aliterature review of animal studies.J Endod.42(2):250-7,2016
非专利文献5:Yang J.,Yuan G.,Chen Z.:Pulp Regeneration:CurrentApproaches and Future Challenges.Front Physiol.:7:58,2016
非专利文献6:He L,Kim SG,Gong Q,Zhong J,Wang S,Zhou X,Ye L,Ling J,MaoJJ.:Regenerative endodontics for adult patients.J Endod.43(9S):S57-S64,2017
非专利文献7:Iohara K,Murakami M,Takeuchi N,Osako Y,Ito M,ishizaka R,Utunomiya S,Nakamura H,Matsushita K,Nakashima M.:A novel combinatorialtherapy with pulp stem cells and granulocyte colony-stimulating factor fortotal pulp regeneration.Stem Cells Transl.Med.2(7):521-533,2013
非专利文献8:Cao Y,Song M,Kim E,Shon W,Chugal N,Bogen G,Lin L,Kim RH,Park NH,Kang MK.:Pulp-dentin Regeneration:Current State and FutureProspects.J Dent Res.94(11):1544-51,2015
非专利文献9:Yang J,Yuan G,Chen Z.:Pulp Regeneration:CurrentApproaches and Future Challenges.Front Physiol.7:58,2016.eCollection2016
非专利文献10:Kawamura R,Hayashi Y,Murakami H,Nakashima M.:EDTAsoluble chemical components and the conditioned medium from mobilized dentalpulp stem cells contain an inductive microenvironment,promoting cellproliferation,migration and odontoblastic differentiation.Stem CellRes.Ther.7(1):77,2016
非专利文献11:The Japanese journal of dermatology and venereology:official organ of the Japanese Dermatological Association,Vol.64,YoshikuniNoguchi,et al.,p.497-506,1954
发明的内容
发明要解决的问题
本发明就是鉴于上述问题而完成的,其目的在于提供一种非细胞根管填料以及使用该非细胞根管填料的非细胞牙体组织再生促进试剂盒,其中该填料在进行牙体组织再生时,在不移植自体或异体干细胞或干细胞来源成分(细胞外分泌蛋白质和外泌体等)的情况下也能够有效地使牙体组织再生。
解决问题的手段
本发明人已经进行了认真的研究,结果发现了促进牙体组织再生的四氢异喹啉化合物。
具体而言,根据本发明一实施方式,提供了一种非细胞根管填料,其包含下式(1)所示的四氢异喹啉化合物或者其在药学上可接受的盐或者它们的溶剂化物。
式中
R1、R2、R3和R4各自独立为-H、-卤素、取代或未取代的C1-6烷基、-OH、-O-C1-6烷基、-SH、-S-C1-6烷基、-COOH、-CO-C1-6烷基、-CO-O-C1-6烷基、-CO-NH-C1-6烷基、-NO2、-NH2、-NH-C1-6烷基、-N(C1-6烷基)2、或者-NH-CO-C1-6烷基,
R5为取代或未取代的C1-6烷基、取代或未取代的C3-10环烷基、取代或未取代的C6-14芳基、-C1-6亚烷基-取代或未取代的C3-10环烷基、或者-C1-6亚烷基-取代或未取代的C6-14芳基,
R6为-H、取代或未取代的-C1-6烷基、或者-Y'-A',
X为C1-6亚烷基,
Y和Y'各自独立为单键或者C1-6亚烷基,
A和A'各自独立为取代或未取代的C6-14芳基或者取代或未取代的3~15元杂环基团,并且
n为0或1。
非细胞根管填料优选包含(+)-4-[[2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙氨基]甲基]-N-异丙基苯胺单富马酸盐或者(+)-N-[3-(甲磺酰基氨基)苄基]-2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙胺单柠檬酸盐。
非细胞根管填料可进一步包含细胞外基质。
非细胞根管填料还可以包含抗CCL11中和抗体和/或ALK5抑制剂。
非细胞根管填料还可以包含选自G-CSF、bFGF和SDF-1中的至少一种趋化因子。
非细胞根管填料可用于幼龄个体或中高龄个体,优选幼龄个体的牙体组织再生。
根据本发明一实施方式,还提供一种牙体组织再生促进试剂盒,该试剂盒包含丝氨酸蛋白酶的预处理剂和非细胞根管填料。
所述牙体组织再生促进试剂盒优选用于中高龄人的牙体组织再生。
所述丝氨酸蛋白酶优选为糜蛋白酶样丝氨酸蛋白酶、更优选为胰蛋白酶。
发明的效果
基于本发明的非细胞根管填料和牙体组织再生促进试剂盒,能够有效地再生牙体组织而无需移植自体或异体牙髓干细胞或其干细胞来源的成分,因此是有用的。
附图说明
图1示出使用了化合物B的非细胞牙髓再生促进试剂盒与使用了SB 328437的非细胞牙髓再生促进试剂盒的比较结果。
图1的A示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像。图1的B示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像(高分辨率)。图1的C示出基于使用了SB 328437的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像。图1D示出基于使用了SB 328437的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色的图像(高分辨率)。图1E示出基于使用了化合物B的非细胞牙髓再生促进试剂盒与使用了SB 328437的非细胞牙髓再生促进试剂盒再生的牙髓量的定量分析结果的图。
图2示出基于使用了化合物B的非细胞牙髓再生促进试剂盒与使用了SB 328437的非细胞牙髓再生促进试剂盒的比较结果。图2的A示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的凝集素染色图像。图2的B示出基于使用了SB 328437的非细胞牙髓再生促进试剂盒处理的牙体组织切片的凝集素染色图像。图2的C示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的PGP9.5免疫染色的图像。图2的D示出基于使用了SB 328437的非细胞牙髓再生促进试剂盒处理的牙体组织切片的PGP9.5免疫染色图像。
图3示出基于使用了化合物B的非细胞牙髓再生促进试剂盒与不使用化合物B的非细胞牙髓再生促进试剂盒的比较结果。图3的A示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像。图3的B示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像(高分辨率)。图3的C示出基于不使用化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像。图3的D示出基于不使用化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像(高分辨率)。图3的E示出定量分析基于使用了化合物B的非细胞牙髓再生促进试剂盒和不使用化合物B的非细胞牙髓再生促进试剂盒再生的牙髓的量的结果的图。
图4示出基于使用了化合物B的非细胞牙髓再生促进试剂盒与不使用化合物B的非细胞牙髓再生促进试剂盒的比较结果。图4的A示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的凝集素染色图像。图4的B示出基于不使用化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的凝集素染色图像。图4的C示出基于使用了化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的PGP9.5免疫染色图像。图4的D示出基于不使用化合物B的非细胞牙髓再生促进试剂盒处理的牙体组织切片的PGP9.5免疫染色的图像。
图5示出基于使用了化合物B的非细胞根管填料的效果在胰蛋白酶预处理和未预处理之间的比较结果。图5的A示出用胰蛋白酶预处理的牙体组织切片的HE染色图像。图5的B示出用胰蛋白酶预处理的牙体组织切片的HE染色的图像(高分辨率)。图5的C示出未经胰蛋白酶预处理的牙体组织切片的HE染色图像。图5的D示出未经胰蛋白酶预处理的牙体组织切片的HE染色的图像(高分辨率)。图5的E示出定量分析用胰蛋白酶预处理和未经胰蛋白酶预处理的基于使用了化合物B的非细胞根管填料的牙髓再生量的结果的曲线图。
图6示出用胰蛋白酶预处理和未经胰蛋白酶预处理的基于使用了化合物B的非细胞根管填料的效果的比较结果。图6的A示出用胰蛋白酶预处理的非细胞牙髓再生促进试剂盒处理的牙体组织切片的凝集素染色的图像。图6的B示出未经胰蛋白酶预处理的非细胞牙髓再生促进试剂盒处理的牙体组织切片的凝集素染色的图像。图6的C示出用胰蛋白酶预处理的牙体组织切片的PGP9.5免疫染色的图像。图6的D示出未经胰蛋白酶预处理的牙体组织切片的PGP9.5免疫染色的图像。
图7示出使用了化合物C的非细胞牙髓再生促进试剂盒与不使用化合物C的非细胞牙髓再生促进试剂盒的比较结果。图7的A示出使用了化合物C的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像。图7的B示出使用了化合物C的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像(高分辨率)。图7的C示出不使用化合物C的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像。图7的D示出不使用化合物C的非细胞牙髓再生促进试剂盒处理的牙体组织切片的HE染色图像(高分辨率)。图7的E示出以牙本质面积为基准并且基于使用了化合物C的非细胞牙髓再生促进试剂盒和不使用化合物C的非细胞牙髓再生促进试剂盒对牙体组织再生进行定量分析的结果的图。图7的F示出以牙本质细胞的密度为基准并且基于使用了化合物C的非细胞牙髓再生促进试剂盒和不使用化合物C的非细胞牙髓再生促进试剂盒对牙体组织再生进行定量分析的结果的图。
具体实施方式
下面将详细描述本发明。然而,本发明不限于本说明书中描述的实施例。
根据第一实施方式,本发明提供了一种非细胞根管填料,其包含下式(1)所示的四氢异喹啉化合物或者其在药学上可接受的盐或者它们的溶剂化物(下面在本说明书中称为“化合物组A”)。
式中,
R1、R2、R3和R4各自独立为-H、-卤素、取代或未取代的C1-6烷基、-OH、-O-C1-6烷基、-SH、-S-C1-6烷基、-COOH、-CO-C1-6烷基、-CO-O-C1-6烷基、-CO-NH-C1-6烷基、-NO2、-NH2、-NH-C1-6烷基、-N(C1-6烷基)2、或者-NH-CO-C1-6烷基,
R5为取代或未取代的C1-6烷基、取代或未取代的C3-10环烷基、取代或未取代的C6-14芳基、-C1-6亚烷基-取代或未取代的C3-10环烷基、或者-C1-6亚烷基-取代或未取代的C6-14芳基,
R6为-H、取代或未取代的-C1-6烷基、或者-Y'-A',
X为C1-6亚烷基,
Y和Y'各自独立为单键或者C1-6亚烷基,
A和A'各自独立为取代或未取代的C6-14芳基或者取代或未取代的3~15元杂环基团,并且
n为0或1。
术语“非细胞”是指不涉及细胞或细胞来源成分(例如细胞外分泌蛋白质和外泌体(exosome))。术语“根管”是指在牙根部容纳牙髓的管。
本实施方式的非细胞根管填料可以包含一种单独的化合物或者两种或多种选自化合物组A的化合物的混合物作为活性成分。化合物组A为CCR3拮抗剂,通过与CCR3结合从而抑制CCL11与CCR3的结合,并可以抑制CCL11的信号传导。
本实施方式中使用的化合物组A的化合物优选为:N-[3-(甲磺酰基氨基)苄基]-2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙胺(WO2008/123582中实施例126,下式(2))、4-[[2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙氨基]甲基]-N-异丙基苯胺(WO2008/123582中实施例138,下式(3))、4-[[2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙氨基]甲基]-N-(2-甲氧基乙基)苯胺(WO2008/123582中实施例150,下式(4)),或者N-(吡啶-4-基)甲基-2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙胺(WO2008/123582中实施例180,下式(5)),或者其在药学上可接受的盐。
本实施方式中使用的化合物组A的化合物特别优选为(+)-4-[[2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙氨基]甲基]-N-异丙基苯胺单富马酸盐(公开于JP2009-173571A中、式(3)的富马酸盐,在本说明书中也称为“化合物B”)、或者(+)-N-[3-(甲磺酰基氨基)苄基]-2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙胺单柠檬酸盐(公开于JP2009-191048A中、式(2)的柠檬酸盐,在本说明书中也称为“化合物C”)。
化合物组A的化合物可以通过适当地将在WO2008/123582中描述的化学合成方法和与其等效的化学合成方法与本领域已知的各种常规方法相结合来制备。
本实施方式的非细胞根管填料可仅由活性成分组成,并且还可以进一步包含选自细胞外基质、抗CCL11中和抗体和/或ALK5抑制剂和/或选自G-CSF、bFGF和SDF-1中的至少一种趋化因子作为任选组分。
可用于本实施例的非细胞根管填料的细胞外基质的实例包括但不限于胶原蛋白、人工蛋白多糖、明胶、水凝胶、纤维蛋白、磷蛋白(phosphophorin)、硫酸乙酰肝素、肝素、层粘连蛋白、纤连蛋白、海藻酸、透明质酸、几丁质、壳聚糖、PLA、PLGA、PEG、PGA、PDLLA、PCL、羟基磷灰石、β-TCP、以及碳酸钙。或者,细胞外基质也可以通过在金属(例如金或钛)基底上涂覆来加以使用。
可用于本实施方式的非细胞根管填料的抗CCL11中和抗体可为本领域已知的任何抗体。抗CCL11中和抗体具有通过结合CCL11从而抑制CCL11与CCR3结合的作用,并可抑制CCL11的信号传导。抗CCL11中和抗体是市售的,且这种市售产品可用于本实施方式中。
可用于本实施方式的非细胞根管填料的ALK5抑制剂可为本领域已知的抑制GDF11信号传导的任何化合物。各种ALK5抑制剂是市售的,且这种市售产品可用于本实施方式。根据本实施方式的ALK5抑制剂的实例包括但不限于以下任意化合物。
可用于本实施例的非细胞根管填料的趋化因子的实例包括但不限于G-CSF、SDF-1、bFGF、TGF-β、NGF、PDGF、BDNF、GDNF、EGF、VEGF、SCF、MMP3、Slit、GM-CSF、LIF和HGF。可以使用选自它们中的一种或两种以上的组合。趋化因子可促进牙周组织周围干细胞的趋化活性。可用于本实施方式的趋化因子优选选自G-CSF、bFGF和SDF-1。所有这些趋化因子均可市售,且此类市售产品可用于本实施方式中。
在本实施例的非细胞根管填料中,各组分的含量可在例如50ng/ml~200μg/ml的范围内、且优选为3μg/ml~100μg/ml。对于活性成分(化合物组A的化合物)与其它任选组分之间的混合比没有特别限制,且可以设为例如10%重量:90%重量~90%重量:10%重量。根据需要,本实施方式的非细胞根管填料可通过与本领域已知的药学上可接受的稀释剂、载体、赋形剂等进行适当组合的成分来制备。
本实施方式的非细胞根管填料既适用于幼龄个体,也适用于中高龄个体,并且优选用于幼龄个体。在这种情况下,对于幼龄个体没有特别限制,例如,1岁以上且29岁以下的人类,出生后1周以上且29周以下的大鼠,或者出生后1周以上且1年以下的犬类。
本实施方式的非细胞根管填料可通过注入到根管中而使用,如在本领域已知的传统牙科根管填料中。
根据第二实施方式,本发明提供了一种牙体组织再生促进试剂盒,其包括丝氨酸蛋白酶的预处理剂和非细胞根管填料。
在本实施方式中,术语“牙体组织”是指包含牙髓、牙本质和根尖牙周组织中的至少一种的组织。
本实施方式的“预处理剂”是在将非细胞根管填料插入根管之前使用。可分解抑制牙体组织和牙周组织再生的因子,和/或将趋化因子或分化促进因子的潜在型(latentform)变为活性型(active form)。
本实施方式的试剂盒中使用的预处理剂包含丝氨酸蛋白酶。丝氨酸蛋白酶是具有丝氨酸残基的蛋白酶(蛋白水解酶),其作为催化残基进行亲核攻击。根据氨基酸序列或构象的相似性,将丝氨酸蛋白酶分为枯草杆菌样丝氨酸蛋白酶和糜蛋白酶样丝氨酸蛋白酶。前者包括枯草杆菌蛋白酶BPN'(subtilisin BPN')、嗜热蛋白酶(thermitase)、蛋白酶K(proteinase K)、羊毛硫抗生素肽酶(lantibiotic peptidase)、科星(kexin)、黄瓜素(cucumisin)等,后者包括胰蛋白酶、糜蛋白酶、凝血酶(thrombin)、Xa因子、弹性蛋白酶(elastase)等。可以在本实施方式中使用的丝氨酸蛋白酶可以是单独的一种酶或从其中选择的两种或更多种酶的组合,并且优选为糜蛋白酶样丝氨酸蛋白酶,更优选为胰蛋白酶。
本实施方式的试剂盒中使用的预处理剂中丝氨酸蛋白酶的浓度没有特别限制,只要该浓度的丝氨酸蛋白酶能够分解抑制牙体组织和牙周组织中的组织再生的因子,和/或将趋化因子或分化促进因子的潜在型(latent form)变为活性型(active form)即可。
浓度例如可以是10μg/ml(0.001%)~50mg/ml(5%)、优选为500μg/ml(0.05%)~5mg/ml(0.5%)。
本实施方式中使用的预处理剂还可以包含纳米微泡。
在本文中,“纳米微泡”是指直径以纳米为单位的气泡,或者在其内腔中包含气体或气体前体且直径以纳米为单位的脂质囊泡。本实施方式的试剂盒中的预处理剂中使用的纳米微泡的直径例如为10~500nm、优选为70~300nm。纳米微泡的直径可通过例如纳米粒子分布测量装置(SALD-7100,日本岛津制作所)测定。可以适当测定纳米微泡的脂质成分、荷电状态、密度、重量等。用于制备纳米微泡的脂质没有特别限制,并且可以是例如磷脂、甘油糖脂和/或鞘糖脂(sphingoglycolipid),或者可以是包含引入此类脂质中的伯氨基、仲氨基、叔氨基或季铵基的阳离子脂质。
预处理剂中的纳米微泡的浓度没有特别限制,并且可以是例如2×107个纳米微泡/cm3~2×109个纳米微泡/cm3。可以通过例如电子自旋共振法(ESR)来定量分析纳米微泡浓度。
预处理可通过将预处理剂注入根管来进行。预处理时间可根据使用的丝氨酸蛋白酶的种类和浓度适当地确定。预处理时间例如可以设为3~30分钟、优选为5~20分钟、更优选为10分钟。
除了预处理剂和非细胞根管填料之外,本实施方式的试剂盒还可以包含附加的缓冲溶液、试剂、说明书等。
本实施方式的试剂盒既可以适用于幼龄(幼年)个体,也适用于中高龄(中老年)个体,优选用于中高龄个体。在这种情况下,对于中龄(中年)个体没有特别限制,并且可以是例如30岁以上和49岁以下的人、出生后30周以上和39周以下的大鼠,再或者出生后2岁以上和4岁以下的犬类。高龄(老年)个体没有特别限制,可以是例如50岁以上的人类、出生后40周以上的大鼠、再或者是出生后5岁以上的犬类。因此,本实施方式的试剂盒优选用于30岁以上的人类、出生后30周以上的大鼠、或者出生后2岁以上的犬类。
实施例
下面,将参考实施例进一步描述本发明。然而,本发明并不限于这些实施例。
实施例1
(幼犬拔髓后牙髓再生)
全麻后,对幼犬(12个月大)上颌、下颌左右前牙进行拔髓。用#55将开口扩大至根尖,然后用5%次氯酸钠溶液和3%过氧化氢溶液交替冲洗,再用生理盐水冲洗,干燥,然后暂时用树脂完全封闭。在拔髓后3~12天,取出临时封闭的树脂,交替清洗开口并再次用生理盐水清洗。
然后,用3%EDTA(Smear Clean,日本齿科药品株式会(Nippon Shika YakuhinCo.,Ltd.))填充根管,处理2分钟,再用生理盐水冲洗并干燥。然后,通过应用胰蛋白酶制剂对根管进行预处理10分钟,然后用生理盐水冲洗,在此前述胰蛋白酶制剂为Francetin T粉(结晶胰蛋白酶2500USP/10mg,持田制药株式会社制造)5mg/ml(0.5%,溶于纳米微泡水中)的制剂,其中该纳米微泡水是用Foamest 8装置(NAC Corp.)制备得到,参见庵原耕一郎(Koichiro Iohara)和中岛美砂子(Misako Nakajima)难治性根尖性牙周炎中含药物纳米气泡水对根管内除菌效果的研究“在犬顽固性根尖疾病模型中,通过纳米微泡增强抗菌纳米聚合物在根管系统中的完整消毒(Enhanced Delivery of AntibacterialNanopolymers with Nanobubbles for the Complete Disinfection of the Root CanalSystem in a Canine Model of Intractable Periapical Disease)”,日本牙科保存学杂志(The Japanese Journal Of Conservative Dentistry),第63卷第1号第73~82页)。
随后,将CCR3拮抗剂(1.25μg的化合物B或0.83μg的SB 328437(TocrisBioscience))作为再生促进化合物以及150ng的G-CSF(Neutrogin,日本中外制药株式会社)作为趋化因子添加到20μl的细胞外基质胶原(Koken Atelocollagen Implant,株式会社高研)中,制备非细胞根管填料,然后将其填充到根管中。然后,使用明胶海绵进行止血(SPONGEL,安斯泰来制药集团),并用玻璃离子粘固剂以及光聚合树脂完全密封空腔。移植后28天拔牙,按常规方法制作纵剖面为5μm的石蜡切片,H-E染色后进行形态学观察。对于每个样品的四个切片,通过测量再生牙髓面积与牙髓腔面积的比率,计算四个样品的平均值来评估再生牙髓的数量。
通过用荧光素标记的Griffonia simplicifolia(Bandeiraea simicifolia)Lectin I(GSL I,BSL I)以及荧光素标记的Galanso Nivalis(Snowdrop)Lectin(GNL)(Vector Laboratories)(20μg/ml)染色28天的标本15分钟来观察血管生成情况,随后进行比较检查。神经突起伸长是将28天标本用PGP9.5(Ultra Clone,1:10000)免疫染色施行比较研究。
结果如图1和2所示。发现含有SB 328437或化合物B作为CCR3拮抗剂的非细胞根管填料可引起富含血管的疏松结缔组织的牙髓再生,而未观察到炎性细胞的浸润或内部吸收(图1A~1D)。再生牙髓与牙髓腔的比率如图1E所示。在含有SB 328437或化合物B作为CCR3拮抗剂的非细胞根管填料中,未观察到牙髓再生量的统计学显著差异(图1E)。进而,在含有SB 328437或化合物B作为CCR3拮抗剂的非细胞根管填料情况下,也均确认到血管新生(图2的A和图2的B)和神经突起伸长(图2的C和图2的D),明确了牙本质样细胞粘附到牙本质侧壁以形成牙本质样硬组织。
实施例2
(有无化合物B对幼犬拔髓后牙髓再生的比较)
全麻后,对幼犬(11个月)的上颌、下颌左右前牙进行拔髓。用#55将开口扩大至根尖,然后用5%次氯酸钠溶液和3%过氧化氢溶液交替冲洗,再用生理盐水冲洗。完全止血后,用纸尖(paper point)彻底干燥根管,并暂时用粘固剂和树脂完全密封。然后,在拔髓后8天,取出该临时密封,交替清洗开口并再次用生理盐水清洗。
然后,用3%EDTA(Smear Clean,日本齿科药品株式会社)填充根管,处理2分钟,再用生理盐水清洗,干燥。然后,通过应用胰蛋白酶制剂对根管进行预处理10分钟,然后用生理盐水清洗,在此前述胰蛋白酶制剂为Francetin T粉(结晶胰蛋白酶2500USP/10mg,持田制药株式会社制造)5mg/ml(0.5%,溶于纳米微泡水中)的制剂,其中该纳米微泡水是用Foamest 8装置(NAC Corp.)制备得到,如实施例1中的描述。随后,将1.25μg的作为再生促进化合物的化合物B以及150ng的作为趋化因子的G-CSF(Neutrogin,日本中外制药株式会社)添加至20μl的细胞外基质胶原(Koken Atelocollagen Implant,株式会社高研)中,制备非细胞根管填料,然后将其填充到根管中。另一方面,除了不含化合物B外,通过与上述相同的程序将具有与上述相同组成的非细胞根管填料填充至根管中作为对照。然后,在其上放置止血用明胶海绵(Spongel,安斯泰来制药集团)用玻璃离子粘固剂以及光聚合树脂完全密封空腔。然后,移植后28天拔除牙齿,按常规方法制作纵剖面为5μm的石蜡切片,用H-E染色,然后以与实施例1相同的方法进行形态学观察。
结果如图3和4所示。使用含有化合物B的非细胞根管填料进行治疗,发现可充分再生牙髓样组织(图3的A和B),而使用不含化合物B的非细胞根管填料治疗仅发现极少量的这种组织再生(图3的C和D)。在两者之间观察到再生牙髓数量在统计学上有显著差异(图3E)。另一方面,可观察到相似的血管新生(图4的A和B)和神经突起伸长(图4的C和D)。这些结果表明化合物B是牙髓组织再生的有效成分。
实施例3
(有无胰蛋白酶预处理对幼犬拔髓后牙髓再生的比较)
全麻后对幼犬(11个月龄)上颌、下颌的左右前牙进行拔髓。用#50将开口扩大到根尖,然后用5%次氯酸钠溶液和3%过氧化氢溶液交替冲洗,再用生理盐水冲洗。完全止血后,用纸尖彻底干燥根管,暂时用粘固剂和树脂封闭。在拔髓后,取出临时密封物,交替清洗开口并再次用生理盐水清洗。然后,用3%EDTA(Smear Clean,日本齿科药品株式会社)填充根管,处理2分钟,再用生理盐水冲洗,干燥。然后,通过应用胰蛋白酶制剂对根管进行预处理10分钟,然后用生理盐水清洗,在此前述胰蛋白酶制剂为Francetin T粉(结晶胰蛋白酶2500USP/10mg,持田制药株式会社制造)5mg/ml(0.5%,溶于纳米微泡水中)的制剂,其中该纳米微泡水是用Foamest 8装置(NAC Corp.)制备得到,如实施例1中的描述。右侧根管不进行预处理(对照组)。
随后,将125μg作为再生促进化合物的化合物B、以及150ng作为趋化因子的G-CSF(Neutrogin,日本中外制药株式会社)加入20μl的细胞外基质胶原(Koken AtelocollagenImplant,株式会社高研)中,以制备非细胞根管填料,然后填充到左右根管中。然后,在其上放置止血用明胶海绵(Spongel,Astellas Pharma Inc.),用玻璃离子粘固剂以及光聚合树脂完全密封空腔。然后,在移植后28天拔除牙齿,按照常规方法制作纵剖面为5μm石蜡切片,用H-E染色,然后用与实施例1相同的方法进行形态学观察。与实施例1中以相同的方式通过BS-1凝集素染色和PGP9.5免疫染色分别证实血管新生和神经突起伸长。
结果如图5和6所示。无论是否进行胰蛋白酶预处理,均能够观察到牙髓组织再生(图5的A~D),胰蛋白酶预处理使再生牙髓的数量略有增加,但无统计学显著差异(图5的E)。此外,胰蛋白酶预处理使更多的牙本质细胞样细胞粘附在牙本质的侧壁上,形成数量稍高的牙本质样硬组织(图5的A和B)。血管新生(图6的A和B)以及神经突起伸长(图6的C和D)在这两种情况下的观察结果相似。这些结果表明,未经胰蛋白酶预处理的非细胞根管填料注射可再生伴随着血管新生和神经突起伸长的牙髓,与胰蛋白酶预处理的根管料一样,可使牙本质样细胞粘附于牙本质侧壁,促进牙本质样细胞的分化和牙本质样硬组织的形成。
实施例4
(有无化合物C对幼犬拔髓后牙髓再生的比较)
全麻后对幼犬(11个月龄)上颌、下颌左右前牙进行拔髓。用#60将开口扩大到根尖,然后用5%次氯酸钠溶液和3%过氧化氢溶液交替冲洗,再用生理盐水冲洗。完全止血后,用纸尖彻底干燥根管,暂时用粘固剂和树脂封闭。在拔髓后,取出该临时密封物,交替冲洗开口并再次用生理盐水冲洗。
然后,用3%EDTA(Smear Clean,日本齿科药品株式会社)填充根管,处理2分钟,再用生理盐水清洗,干燥。然后,通过应用胰蛋白酶制剂预处理根管10分钟,再用生理盐水清洗,在此前述胰蛋白酶制剂为Francetin T粉(结晶胰蛋白酶2500USP/10mg,持田制药株式会社制造)5mg/ml(0.5%,溶于纳米微泡水中)的制剂,其中该纳米微泡水是用Foamest 8装置(NAC Corp.)制备得到,如实施例1中的描述。随后,将1.2μg的作为再生促进化合物的化合物C以及150ng的作为趋化因子的G-CSF(Neutrogin,日本中外制药株式会社)添加至20μl的细胞外基质胶原(Koken Atelocollagen Implant,株式会社高研)中,制备非细胞根管填料,然后将其填充到根管中。另一方面,将除不含化合物C外组成与上述相同的非细胞根管填料按上述相同步骤充填于根管中作为对照。然后,在其上放置止血用明胶海绵(Spongel,安斯泰来制药集团)用玻璃离子粘固剂以及光聚合树脂完全密封空腔。然后,在移植后28天拔除牙齿,按常规方法制作纵剖面为5μm的石蜡切片,用H-E染色,然后以与实施例1相同的方法进行形态学观察。针对每三个样本的一个切片,通过测量牙本质面积相对于牙齿面积的比率并计算三个样本的平均值来评估牙本质的面积。针对每三个样本的一个切片,通过测量距离根管侧壁1mm范围内的牙本质细胞数量来计算牙本质细胞的密度。
结果如图7所示。
当使用含化合物C的非细胞根管填料处理时,发现可以充分再生牙髓样组织(图7的A和B),然而在使用不含化合物C的非细胞根管填料处理时,仅发现以非常少的量再生此类组织(图7的C和D)。与不含化合物C的非细胞根管填料相比,含化合物C的非细胞根管填料的牙本质面积增加(图7的E)、牙本质细胞密度增大(图7的F),表明化合物C是牙髓组织再生的有效成分。
Claims (14)
1.一种非细胞根管填料,其包含由下式(1)表示的四氢异喹啉化合物或其在药学上可接受的盐或者它们的溶剂化物,
式中
R1、R2、R3和R4各自独立地为-H、-卤素、取代或未取代的C1-6烷基、-OH、-O-C1-6烷基、-SH、-S-C1-6烷基、-COOH、-CO-C1-6烷基、-CO-O-C1-6烷基、-CO-NH-C1-6烷基、-NO2、-NH2、-NH-C1-6烷基、-N(C1-6烷基)2、或者-NH-CO-C1-6烷基,
R5为取代或未取代的C1-6烷基、取代或未取代的C3-10环烷基、取代或未取代的C6-14芳基、-C1-6亚烷基-取代或未取代的C3-10环烷基,或者-C1-6亚烷基-取代或未取代的C6-14芳基,
R6为-H、取代或未取代的-C1-6烷基、或者-Y'-A',
X为C1-6亚烷基,
Y和Y'各自独立为单键或C1-6亚烷基,
A和A'各自独立为取代或未取代的C6-14芳基或者取代或未取代的3~15元杂环基团,并且
n为0或1。
2.如权利要求1所述的非细胞根管填料,其包含(+)-4-[[2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙氨基]甲基]-N-异丙基苯胺单富马酸盐或(+)-N-[3-(甲磺酰氨基)苄基]-2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙胺单柠檬酸盐。
3.如权利要求1或2所述的非细胞根管填料,其还包含细胞外基质。
4.如权利要求1至3中任一项所述的非细胞根管填料,其还包含抗CCL11中和抗体和/或ALK5抑制剂。
5.如权利要求1至4中任一项所述的非细胞根管填料,其还包含选自G-CSF、bFGF和SDF-1中的至少一种趋化因子。
6.如权利要求1至5中任一项所述的非细胞根管填料,其用于年轻个体的牙组织再生。
7.一种牙组织再生促进试剂盒,其包含预处理剂以及非细胞根管填料,
所述预处理剂含有丝氨酸蛋白酶,
所述非细胞根管填料包含由下式(1)表示的四氢异喹啉化合物或其在药学上可接受的盐或者它们的溶剂化物,
式中,
R1、R2、R3和R4分别为-H、-卤素、取代或未取代的C1-6烷基、-OH、-O-C1-6烷基、-SH、-S-C1-6烷基、-COOH、-CO-C1-6烷基、-CO-O-C1-6烷基、-CO-NH-C1-6烷基、-NO2、-NH2、-NH-C1-6烷基、-N(C1-6烷基)2、或者-NH-CO-C1-6烷基,
R5为取代或未取代的C1-6烷基、取代或未取代的C3-10环烷基、取代或未取代的C6-14芳基、-C1-6亚烷基-取代或未取代的C3-10环烷基、或者-C1-6亚烷基-取代或未取代的C6-14芳基,
R6为-H、取代或未取代的-C1-6烷基、或者-Y'-A,
X为C1-6亚烷基,
Y和Y'各自独立为单键或C1-6亚烷基,
A和A'各自独立为取代或未取代的C6-14芳基或者取代或未取代的3~15元杂环基团,并且
n为0或1。
8.如权利要求7中所述的牙组织再生促进试剂盒,其包含(+)-4-[[2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙氨基]甲基]-N-异丙基苯胺单富马酸盐或(+)-N-[3-(甲磺酰基氨基)苄基]-2-[6-氟-3-(4-氟苄基)-3,4-二氢异喹啉-2(1H)-基]乙胺单柠檬酸盐。
9.如权利要求7或8所述的牙组织再生促进试剂盒,其中所述非细胞根管填料还包含细胞外基质。
10.如权利要求7至9中任一项所述的牙组织再生促进试剂盒,其中所述非细胞根管填料还包含抗CCL11中和抗体和/或ALK5抑制剂。
11.如权利要求7至10中任一项所述的牙组织再生促进试剂盒,其中,
所述非细胞根管填料还包含选自G-CSF、bFGF和SDF-1中的至少一种趋化因子。
12.如权利要求7至11中任一项所述的牙组织再生促进试剂盒,其中,
所述丝氨酸蛋白酶是糜蛋白酶样丝氨酸蛋白酶。
13.如权利要求7至12中任一项所述的牙组织再生促进试剂盒,其中,
所述糜蛋白酶样丝氨酸蛋白酶是胰蛋白酶。
14.如权利要求7至13中任一项所述的牙组织再生促进试剂盒,其用于中老年个体的牙组织再生。
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