CN1052045A - 牙周组织再生促进剂的制备方法 - Google Patents
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Abstract
牙周组织再生促进剂，其特征在于含有选自N-
乙酰基-D-萄糖胺、N-乙酰基-D-半乳糖胺、N-乙
酰基-D-甘露糖胺以及它们在α-或者β-1，4-上结
合的低聚糖的N-乙酰化氨基糖作为活性成分。
Description
本发明涉及为使由于牙周炎而被破坏的牙龈膜再生，促进正常的牙龈与结合组织间的附着而用的药剂。
过去，作为牙周炎的治疗方法，主要通过刮治术等，以进行机械性地除去牙周囊内的斑块，或者其症状严重时，进行牙周外科方面的处置，而且最近，用抗生物质的化学疗法也在试验阶段。这些疗法，对于阻止牙周炎的发展是有效的措施，但不是积极修复，再生所破坏的牙周组织的方法，而临床症状的改善始终要依靠生体的自己治愈力。
牙周组织是指硬组织（牙龈）和软组织（牙肉），通过牙龈膜纤维性的牢固结合而附着的，具有其他组织中所看不到的结构，但如果由于牙周炎使牙周组织被破坏，在牙龈膜再生之前，牙肉表面的上皮细胞将破坏的部分包覆住（上皮的道恩氏综合征），因此只发生上皮组织和牙龈的疏松结合。因此，延迟牙周组织的修复、再生，并高频率地发生牙肉的退缩。对此，为了达到正常的纤维性结合，从过去已经知道的采用（1）通过柠檬酸的龈面处理，（2）细胞附着性糖蛋白的丝蛋白（fibronectin）对局部的应用（3）通过生体适合性高的遮断膜，抑制上皮的道恩氏综合征的诱导组织再生法（GTR法），但存在着以下问题（1）是对细胞的为害性，（2）作为高分子丝蛋白的稳定性，抗原性，（3）是为了摘出而必须再进行手术以及由于手术者的差而产生的问题，因此，希望有安全性，易于剂型和有效性兼顾的促进牙周组织再生的药剂。
本发明的目的在于提供上述的安全性，稳定性以及有效性方面优异的牙周组织再生剂。
本发明提供牙周组织的再生剂，其特征在于，含有从N-乙酰基-D-葡糖胺，N-乙酰基-D-半乳糖胺，N-乙酰基-D-甘露糖胺，以及这些氨基糖的α-或者β-1，4结合的低聚糖群组中选出的N-乙酰化氨基糖作为活性成分。
这些N-乙酰化氨基糖，在特公昭58-11927号中，本申请人公开了用于抑制齿垢向牙齿附着的口腔用组合物的有效成份。但尚没有报导过将其应用于牙周炎的治疗。然而，本发明者们意外地发现，这些N-乙酰化氨基糖具有促进牙周组织的再生效果，并可用于牙周炎的治疗上。
在本发明中用作为活性成份的N-乙酰基-D-萄糖胺是构成昆虫或甲壳类的壳的多糖壳质的主成份，N-乙酰基-D-半乳糖胺为软骨素硫酸的主成份，与N-乙酰基-D-甘露糖胺同时存在于自然界。另外，N-乙酰基-D-萄糖胺低聚物是通过将甲壳质加水分解，中和，脱盐之后，以凝胶过滤法分离精制而得出的。N-乙酰基-D-半乳糖胺低聚物是，将D-半乳糖胺主要结合在α-1，4的α-1，4聚半乳糖胺，进行加水分解，乙酰化后，以凝胶过滤法离析精制。
这些物质是来源于生体的物质，安全性非常高，例如，对于培养的人牙龈膜细胞的细胞毒性为10mg/ml以上，并在所观察的有效性的10～100μg/mg范围内完全看不到增殖阻碍。
因此，本发明的牙周组织再生促进剂，根据通常的制剂技术，可以把有效且非毒性量的该N-乙酰化氨基糖与医药上所允许的载体，例如，溶剂，等渗化剂，乳化剂，悬浮剂，稳定剂结合起来可以作为外用剂（例如，液剂，乳液，凝胶剂）。本发明涉及的牙周组织再生促进剂，可以直接投放在通过牙周外科处置、或者龈面平滑处理后的牙龈面及剥离齿肉面上。投给量应根据所治疗的症状，部位可以适当地增减，通常，若将该N-乙酰化氨基糖，以10～100μg/ml（0.001～0.01%）的浓度，一次0.1～3ml程度，一日1～3次涂敷于患处，或者注射，就能发挥所希望的牙周组织再生促进效果。
下面举实施例进一步详细说明本发明。
实施例1
成分 量
N-乙酰基-D-甘露糖胺 0.002克
（西格马社制）
生理盐水 调节全量为100克
将这些成份进行混合溶解，无菌过滤后，得到液剂。
实施例2
成分 量
N-乙酰基-D-半乳糖胺二聚物 0.01克
（船越药品）
硬脂酸 2克
十六醇 0.5克
羊毛脂 2克
十四碳烷酸异丙酯 2克
三十碳烷 3克
流动石蜡 8克
聚氧化乙烯十六烷基醚 1.7克
三乙醇胺 1克
甘油 4克
防腐剂 适量
精制水 调节到全量为100克
用这些成份，按照常规法得到乳液。
实施例3
成份 量
N-乙酰基-D萄糖胺三聚物 0.01克
月桂基硫酸钠 0.2克
羧基甲基纤维素 2克
甘油 40克
精制水 调节到全量为100克
将这些成份进行混合，得到凝胶剂。
试验N-乙酰基-D-萄糖胺、N-乙酰基-D-半乳糖胺，N-乙酰化-D-甘露糖胺以及这些氨基糖在α-或者β-1，4结合而成的低聚糖的牙周组织再生促进作用。下面表示其结果。
（1）对于牙龈膜纤维芽细胞的运动性的作用
从拔去人齿后而残存的牙龈膜初次培养牙龈膜纤维芽细胞，从齿肉组织初次培养上皮细胞，通过使用具有孔径8微米的滤器的48孔显微腔室法，测定了具有各种N-乙酰化氨基糖及低聚糖对于牙龈膜纤维芽细胞及齿肉上皮细胞的趋化性活性。
在腔室的上室加入5.0×105个/ml的细胞悬浮液，而在下室中，以10～100μg/ml的比例加入各种N-乙酰化氨基糖及低聚糖，并在37℃培养4小时。然后固定滤器，Diff-Quick染色后，在显微镜下计数游走至滤器底部的细胞数。作为对照，不加检体同样地进行试验。表1表示了将对照的系数值作为100%的情况下添加N-乙酰化氨基糖以及低聚糖时的相对比例。
表1
| 检体 | 浓度 | 牙根膜纤维芽细胞 | 齿肉上皮细胞 |
| 对照 | 100 | 100 | |
| N-乙酰基-D-萄糖胺 | 10μg/ml100μg/ml | 114135 | 10197 |
| N-乙酰基-D-半乳糖胺 | 10μg/ml100μg/ml | 131168 | 106107 |
| N-乙酰基-D-甘露糖胺 | 10μg/ml100μg/ml | 145176 | 9195 |
| N-乙酰基-D-萄糖氨基二聚物 | 10μg/ml100μg/ml | 110128 | 100101 |
| N-乙酰基-D-萄糖氨基三聚物 | 10μg/ml100μg/ml | 140145 | 11099 |
| N-乙酰基-D-?半乳糖氨基二聚物 | 10μg/ml100μg/ml | 131160 | 97102 |
| N-乙酰基-D-半乳糖氨基三聚物 | 10μg/ml100μg/ml | 145161 | 113110 |
如表1所示，N-乙酰基-D-萄糖胺及它的二聚物、三聚物、N-乙酰基-D-半乳糖胺及它的二聚物、三聚物，进而N-乙酰基-D-甘露糖胺，哪一种都具有对于牙龈膜纤维芽细胞的特异的趋化活性，而对于齿肉上皮细胞几乎不起作用。其结果，很明显，这些药剂具有只使构成牙周组织再生的中心的牙龈膜纤维芽细胞比较有选择地游走到病变部位的作用。
（2）对于牙龈膜纤维芽细胞的增殖性的作用
测定了各种N-乙酰化氨基糖以及低聚糖对于牙龈膜纤维芽细胞的增殖性的作用。
在直径35mm的组织培养用皿上播种牙龈膜纤维芽组织3.0×104个，在37℃培养1日后，以100μg/ml的比例加入各种N-乙酰化氨基糖以及低聚糖，并进一步在37℃培养2日。然后用0.15%胰蛋白酶溶液，将细胞从培养皿剥离，通过血球计算盘计测细胞数。作为对照，不加检体，同样地进行了试验。
各检体在培养皿中所增殖的细胞数表示于表2。
第2表
| 检体 | 细胞数／培养皿 |
| 对照N-乙酰基-D-萄糖胺N-乙酰基-D-半乳糖胺N-乙酰基-D-甘露糖胺N-乙酰基-D-萄糖氨基二聚物N-乙酰基-D-萄糖氨基三聚物N-乙酰基-D-半乳糖氨基二聚物N-乙酰基-D-半乳糖氨基三聚物 | 1.1×1041.3×1041.6×1041.8×1041.2×1041.2×1041.7×1041.9×104 |
如表2所示，N-乙酰基-D-萄糖胺及它的二聚物、三聚物、N-乙酰基-D-半乳糖胺及它的二聚物，三聚物，以及N-乙酰基-D-甘露糖胺，哪一种都可提高牙龈膜纤维芽细胞的增殖性。
（3）对于狗牙齿肉剥离搔爬手术后的牙周组织再生过程的作用
用病理组织学方面的定量评价法，研究了N-乙酰化氨基糖以及低聚糖对于狗牙齿肉剥离搔爬手术后的牙周组织再生过程的作用。通过火花电灼术等，在确立健康的牙周组织的上下腭小臼齿部，根据常法施行了齿肉剥离搔爬手术后。此时，为了作为以后的病理组织学方面定量化的基准点，在施行齿槽骨的削除前后，在龈面上作一个称作切痕的基准点。检体为以实施例3中所示的同样的凝胶剂，在左侧上下腭所露出的龈面上，对于每一部位投给50mg，而作为对照，在右侧上下腭投给了没有配合药物的凝胶剂。手术后复位齿肉辨，通过缝合与包扎施以一周的保护。评价是手术后的第4周，取被检部位，根据常法作成组织标本之后，在显微镜下，用测微目镜测定各部位间的距离，以下面的基准进行了定量。
1：上皮的道恩氏生长率（%）
从骨削除前的切痕下缘
(到上皮的最根尖侧的距离)/(削除骨的长度) ×100
2：纤维性附着率（%）
(纤维垂直及倾斜部分的长度)/(削除骨的长度) ×100
结果示于表3中。
第3表
| 检体 | 浓度（％） | 上皮的道恩氏生长率 | 纤维性付着率 |
| 对照N-乙酰基-D-半乳糖胺N-乙酰基-D-甘露糖胺N-乙酰基-D-萄糖氨基三聚物N-乙酰基-D-半乳糖氨基三聚物 | 0.010.010.010.01 | 12.611.810.710.410.2 | 23.135.240.337.841.1 |
如表3所示，N-乙酰基-D-半乳糖胺及它的三聚物，N-乙酰基-D-甘露糖胺，以及N-乙酰基-D-萄糖氨基三聚物，只稍微抑制上皮的道恩氏生长，而对于纤维性附着率，表示了明显的促进作用。
如从上面的结果明显看出，N-乙酰化氨基糖以及低聚糖具有优异的牙周组织再生促进作用。
Claims (2)
1、一种生产牙周组织再生促进剂的方法，包括，将有效量的选自N-乙酰基-D-萄糖胺、N-乙酰基-D-半乳糖胺、N-乙酰基-D-甘露糖胺以及他们的低聚糖化物的N-乙酰化氨基糖与医药上所允许的载体进行混合。
2、根据权利要求1的方法，其中混合0.001～0.01%的N-乙酰化的氨基糖。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP220031/89 | 1989-08-25 | ||
| JP1220031A JPH0383927A (ja) | 1989-08-25 | 1989-08-25 | 歯周組織再生促進剤 |
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| Publication Number | Publication Date |
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| CN1052045A true CN1052045A (zh) | 1991-06-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN90107588A Pending CN1052045A (zh) | 1989-08-25 | 1990-08-25 | 牙周组织再生促进剂的制备方法 |
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| Country | Link |
|---|---|
| JP (1) | JPH0383927A (zh) |
| CN (1) | CN1052045A (zh) |
| WO (1) | WO1991002530A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106061485A (zh) * | 2013-12-27 | 2016-10-26 | 高露洁-棕榄公司 | 使用糖类的益生性口腔护理方法 |
| CN109152936A (zh) * | 2016-05-26 | 2019-01-04 | 3M创新有限公司 | 治疗牙膏及相关方法及试剂盒 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5362480A (en) * | 1991-12-31 | 1994-11-08 | Lever Brothers Company, Division Of Conopco, Inc. | Oral hygiene compositions containing amino sugars as antiplaque agents |
| US5286480A (en) * | 1992-06-29 | 1994-02-15 | The Procter & Gamble Company | Use of N-acetylated amino acid complexes in oral care compositions |
| CN1173706C (zh) | 2001-02-28 | 2004-11-03 | 中国人民解放军第三军医大学 | N-乙酰-d-氨基葡萄糖在制备治疗宫颈糜烂药物中的应用 |
| CN1199645C (zh) | 2002-08-13 | 2005-05-04 | 中国人民解放军第三军医大学 | N－乙酰－d－氨基葡萄糖在制备治疗泌尿生殖道感染药物中的应用 |
| CN1210038C (zh) | 2003-03-27 | 2005-07-13 | 中国人民解放军第三军医大学 | N－乙酰氨基葡萄糖在制备用于治疗毒物和药物中毒致脏器损伤的药物中的应用 |
| PL1951184T3 (pl) | 2005-11-09 | 2012-06-29 | Valeant Pharmaceuticals Int Inc | Kompozycje do wybielania zębów i sposoby |
| US20100266989A1 (en) | 2006-11-09 | 2010-10-21 | Klox Technologies Inc. | Teeth whitening compositions and methods |
| EP3205355A1 (en) | 2008-11-07 | 2017-08-16 | KLOX Technologies, Inc. | Combination of an oxidant and a photoactivator |
| PL2453922T3 (pl) | 2009-07-17 | 2018-03-30 | Klox Technologies Inc. | Przeciwbakteryjna doustna kompozycja |
| US20130281913A1 (en) | 2012-04-20 | 2013-10-24 | Klox Technologies Inc. | Biophotonic compositions and methods for providing biophotonic treatment |
| US11116841B2 (en) | 2012-04-20 | 2021-09-14 | Klox Technologies Inc. | Biophotonic compositions, kits and methods |
| EP2895139B1 (en) | 2012-09-14 | 2019-10-23 | Bausch Health Companies Inc. | Methods for teeth whitening |
| US20140276354A1 (en) | 2013-03-14 | 2014-09-18 | Klox Technologies Inc. | Biophotonic materials and uses thereof |
| RU2016103321A (ru) | 2013-07-03 | 2017-08-08 | Клокс Текнолоджиз Инк. | Композиции и способы для лечения незаживающих ран |
| KR20160140716A (ko) | 2014-04-01 | 2016-12-07 | 클록스 테크놀로지스 인크. | 조직 필러 조성물 및 사용 방법 |
| AU2015337786B2 (en) | 2014-10-31 | 2020-03-26 | Klox Technologies Inc. | Photoactivatable fibers and fabric media |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5811927B2 (ja) * | 1978-11-16 | 1983-03-05 | サンスタ−株式会社 | 口腔組成物 |
| JPS60142923A (ja) * | 1983-12-28 | 1985-07-29 | Lion Corp | 歯周病薬 |
| JPS62294607A (ja) * | 1986-06-13 | 1987-12-22 | Kanebo Ltd | 口腔用組成物 |
-
1989
- 1989-08-25 JP JP1220031A patent/JPH0383927A/ja active Pending
-
1990
- 1990-08-22 WO PCT/JP1990/001066 patent/WO1991002530A1/ja not_active Ceased
- 1990-08-25 CN CN90107588A patent/CN1052045A/zh active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106061485A (zh) * | 2013-12-27 | 2016-10-26 | 高露洁-棕榄公司 | 使用糖类的益生性口腔护理方法 |
| US11419806B2 (en) | 2013-12-27 | 2022-08-23 | Colgate-Palmolive Company | Prebiotic oral care methods using a saccharide |
| CN109152936A (zh) * | 2016-05-26 | 2019-01-04 | 3M创新有限公司 | 治疗牙膏及相关方法及试剂盒 |
| CN109152936B (zh) * | 2016-05-26 | 2021-08-27 | 3M创新有限公司 | 治疗牙膏及相关方法及试剂盒 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0383927A (ja) | 1991-04-09 |
| WO1991002530A1 (fr) | 1991-03-07 |
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