TWI660745B - 含有羧酸之益生質口腔保健組成物 - Google Patents
含有羧酸之益生質口腔保健組成物 Download PDFInfo
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- TWI660745B TWI660745B TW103145374A TW103145374A TWI660745B TW I660745 B TWI660745 B TW I660745B TW 103145374 A TW103145374 A TW 103145374A TW 103145374 A TW103145374 A TW 103145374A TW I660745 B TWI660745 B TW I660745B
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- oral
- bacteria
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- oral health
- acid
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- 125000000468 ketone group Chemical group 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002613 leucine derivatives Chemical class 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 229930007744 linalool Natural products 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
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- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
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- 229930007503 menthone Natural products 0.000 description 1
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- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
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- 229920000136 polysorbate Polymers 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
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- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
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- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 229940093928 potassium nitrate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 229960003415 propylparaben Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- NJGBTKGETPDVIK-UHFFFAOYSA-N raspberry ketone Chemical compound CC(=O)CCC1=CC=C(O)C=C1 NJGBTKGETPDVIK-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000002310 reflectometry Methods 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 235000019982 sodium hexametaphosphate Nutrition 0.000 description 1
- 229940079862 sodium lauryl sarcosinate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- UGTZMIPZNRIWHX-UHFFFAOYSA-K sodium trimetaphosphate Chemical compound [Na+].[Na+].[Na+].[O-]P1(=O)OP([O-])(=O)OP([O-])(=O)O1 UGTZMIPZNRIWHX-UHFFFAOYSA-K 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- ADWNFGORSPBALY-UHFFFAOYSA-M sodium;2-[dodecyl(methyl)amino]acetate Chemical compound [Na+].CCCCCCCCCCCCN(C)CC([O-])=O ADWNFGORSPBALY-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 159000000008 strontium salts Chemical class 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- 150000005846 sugar alcohols Polymers 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical class NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- LLZRNZOLAXHGLL-UHFFFAOYSA-J titanic acid Chemical compound O[Ti](O)(O)O LLZRNZOLAXHGLL-UHFFFAOYSA-J 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- YARHBRUWMYJLHY-UHFFFAOYSA-Q triazanium;iron(3+);hexacyanide Chemical compound [NH4+].[NH4+].[NH4+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] YARHBRUWMYJLHY-UHFFFAOYSA-Q 0.000 description 1
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- 230000035899 viability Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
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- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Abstract
本發明提供一種包含式I之羧酸的口腔保健組成物:
其中:R1是H,或經取代或未經取代的烷基;且R2是H、OH或NH2;或其中該式I羧酸是反丁烯二酸或N-乙醯神經胺酸;其用途在於:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的在口腔中促進對口腔健康有良性影響的細菌之生物膜形成;或(c)維持和或重建健康的口腔微生物相。
Description
本發明提供一種包含式I之羧酸的口腔保健組成物:
其中:R1是H,或經取代或未經取代的烷基;且R2是H、OH或NH2;或其中該式I羧酸是反丁烯二酸或N-乙醯神經胺酸;其用途在於:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的在口腔中促進對口腔健康有良性影響的細菌之生物膜形成;或(c)維持和或重建健康的口腔微生物相。
口腔含有許多相異的細菌菌種。某些口腔的病原性細菌菌種,例如牙齦卟啉單胞菌(Porphyromonas gingivalis)、福賽斯坦納菌(Tannerella forsythia)和伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans),已被暗示造成牙周疾病的發生,如:牙周炎、牙齦炎、壞死性牙周炎、壞死性牙齦炎和植體周圍炎。某些口腔致病
細菌種已被暗示會造成齲齒(例如變異鏈球菌(Streptococcus mutans))。
吾人相信某些口腔菌種有益於維持牙周組織的健康。不受限於任何理論,吾人相信這些有益的口腔細菌會干擾口腔上皮病原性口腔細菌的移生。例如研究已顯示口腔鏈球菌(Streptococcus oralis)、緩症鏈球菌(Streptococcus mitts)和唾液鏈球菌(Streptococcus salivarius)在試管中對於伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans)於上皮細胞之移生有抑制作用(W.Teughels等人,《牙科研究雜誌》,第86期(7),第611-617頁,2007年)。研究亦已顯示利用犬的模型,在牙根整平之後施用益菌到牙周袋會延緩和降低牙周袋被病原性細菌再移生(W.Teughels等人,《牙科研究雜誌》,第86期(11),第1078-1082頁,2007年)。有益的細菌口腔鏈球菌(Streptococcus oralis)、緩症鏈球菌(Streptococcus mitis)和唾液鏈球菌(Streptococcus salivarius)亦已被顯示能抑制伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans)誘發人類口腔角質化細胞株HOK-18A產生發炎細胞激素介白素-8(IL-8),該發炎反應與牙周炎相關的組織破壞有牽連(I.Sliepen等人,《牙科研究雜誌》,第88期(11),第1026-1030頁,2009年)。
吾人相信選擇性的刺激有益口腔細菌能對口腔健康提供確切的預防方法,例如在預防牙周炎方面。
在第一方面,本發明提供一種包含式I之羧酸的口腔保健組成物:
其中:R1是H,或為經取代或未經取代的烷基;且R2是H、OH或NH2;或其中式I的羧酸是反丁烯二酸或N-乙醯神經胺酸;其被用於:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的在口腔中促進對口腔健康有良性影響的細菌之生物膜形成;或(c)維持和或重建健康的口腔微生物相。
視需要,該羧酸係以該口腔保健組成物重量為基準,以0.01wt%到10wt%的量存在於該組成物中。
視需要,該羧酸以該口腔保健組成物體積為依據,以5μmol/ml到30μmol/ml的量存在於該組成物中。
視需要,R2是H。
視需要,R2是OH。
視需要,R2是NH2。
視需要,該羧酸是酸性胺基酸。而且視需要,該酸性胺基酸是是一種L-胺基酸。還更視需要,該酸性胺基酸是天冬胺酸或麩胺酸。
視需要,R1是H。
視需要,R1是未經取代的烷基.。而且視需要,R1是未經取代的C1-C4烷基。還更視需要,該羧酸是L-乳酸。
視需要,R1包含一個醣殘基。而且視需要,該醣殘基是吡喃半乳糖殘基。還更視需要,該吡喃半乳糖殘基是α-D-吡喃半乳糖殘基。而更視需要,該羧酸是蜜二糖酸。
視需要,R1包含至少一個COOR3基,其中R3是H或C1-4烷基。
視需要,R1包含至少一個C(O)COOH基。
視需要,R1是(CH2)nCOOR3,其中n是從1到5的數。而且視需要,n是1。還更視需要,該羧酸是琥珀酸或L-蘋果酸。
視需要,該羧酸是琥珀酸單甲酯。
視需要,R1是(CH2)mC(O)COOH,其中m是從1到4的數。而且視需要,該羧酸是α-酮基戊二酸。
視需要,R1包含兩個COOH基。而且視需要,該羧酸是檸檬酸。
視需要,該組成物是一種潔牙劑、牙膏、牙膠、牙粉、漱口水、口腔潤洗劑、錠劑、藥片、噴霧劑、口香糖或薄膜。
視需要,該組成物尚包含至少一種對口腔健康具有良性影響之細菌。而且視需要,該對於口腔健康具有益效果之細菌菌種係選自緩症鏈球菌(Streptococcus mitis)、唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、小韋榮氏球菌(Veillonella parvula)、格氏鏈球菌(Streptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)和內氏放線菌(Actinomyces naeslundii)及其組合。
視需要,該口腔保健組成物係用於預防牙齦炎、牙周炎、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎、壞死性牙周炎和齲齒中之一種或多於一種病狀。
在第二方面,本發明提供一種在施用對象口腔中選擇性的促進以下項目之方法:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的促進對口腔健康有良性影響的細菌之生物膜形成;該方法包括將施用對象的口腔與根據本發明的口腔保健組成物接觸。
第三方面,本發明提供在施用對象的口腔中維持和/或重建健康的口腔微生物相的方法,該方法包括將施用對象的口腔與根據本發明的口腔保健組成物接觸。
第四方面,本發明提供預防施用對象罹患牙齦炎、牙周炎、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎、壞死性牙周炎和齲齒中之一種或多於一種病狀的方法,該方法包括將施用對象的口腔與根據本發明的口腔保健組成物接觸。
第五方面,本發明提供式I之羧酸在口腔保健組成物中的用途:
其中:R1是H,或是經取代或未經取代的烷基,且R2是H、OH或NH2;或其中式I的羧酸是反丁烯二酸或N-乙醯神經胺酸;用於:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的在口腔中促進對口腔健康有良性影響的細菌之生物膜形成;或(c)維持和或重建施用對象之健康的口腔微生物相;或(d)預防施用對象罹患牙齦炎、牙周炎、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎、壞死性牙周炎和齲齒中之一種或多於一種。
視需要,該羧酸在與對口腔健康有良性影響的細菌和病原性的口腔細菌培育24小時後,相對於病原性口腔細菌的生長、代謝活性或移生,其選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生。
視需要,該羧酸在與對口腔健康有良性影響的細菌和病原性的口腔細菌培育48小時後,相對於病原性口腔細菌的生長、代謝活性或移生,其選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生。
本發明的更多可應用性的領域從本發明書之後提供的詳細說明顯然可知。吾人應瞭指示本發明的較佳實施例時所提出的解詳細說明與特定實例係僅意圖達到說明的目的而無意對本發明的範疇作出限制。
以下較佳實例的說明本質上僅作為範例且毫不意圖對本發明、其應用或用途作限制。
通貫本說明書,以節略方式使用範圍來說明在此範圍的每一個數值。任何在該範圍的數值均可被挑選作為該範圍的終端。此外,所有本說明書中引用的參考文獻均以其完整內容併入本說明書中。在本說明書和引用文獻的定義有衝突的情況下,則本說明書控制該定義。
除非另有指明,否則所有在本說明書和在專利說明書之他處所表示的百分率和用量應被瞭解為係指重量百分率。給定的用量是依照物質的有效重量而定。
在本說明書中所使用的,「口腔」的表示法不僅包括腔洞本身且亦包括唾液、牙齒、牙齦、牙周袋、頰、舌、粘膜、扁桃腺、任何植體和任何被置入口腔的裝置或結構。扁桃腺提供可能產生口臭之厭氣性細菌生長的貯存器(扁桃腺結石)。
如本說明書中所使用的,「健康的口腔微生物相」詞組係指口腔在非疾病狀態時(例如,當沒有牙周疾病存在,例如牙齦炎、牙周炎、齲齒、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎和/或壞死性牙周炎)口腔中的微生物群聚,亦即與健康關聯的微生物相。
「有益的細菌」一詞涵蓋以較高數量或比率存在於健康口腔,但是以低數量或比率存在於口腔疾病(例如牙齦炎、牙周炎、齲齒、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎和壞死性牙周炎)條件下的細菌。本詞語亦包括口腔或非口腔來源的細菌,業經預防或治療口腔疾病被證明對口腔健康具有利影響者,其可能已存在於口腔或特意被導入口腔(例如呈益生質)。有益的細菌可藉其存在或代謝活性:造成:降低病原性口腔細菌的數目或比率;降低發炎和發炎過程;降低病原性菌種的代謝活性;降低病原性細菌產生的毒性因子之產生或抑制該因子;降低或抑制生物膜產生;佔據否則可能被病原體移生的地位;限制病原體黏附到口腔表面的能力;影響病原體的可存活性、代謝活性或生長;降低病原體生產毒性因子的能力;破壞病原體或口腔微生物相所生產的毒性因子;和/或調節宿主對病原性菌種的反應。如以上所討論的,吾人相信這些有益的口腔細菌會干擾口腔上皮被病原性口腔細菌移生。吾人相信選擇性的刺激有益的口腔細菌會對口腔健康提供有效的預防方法,例如預防牙周炎。
細菌需要某些基質已使其能生長、增殖、具有代謝活性且能移生。某些基質可被某些微生物(例如:細菌)選擇性使用,以遂其生長、代謝、增殖和移生,並且因而直接或間接的抑制其他微生物的生長。本發明的研究者探究藉由提供口腔益菌適當的生長/增殖基質,選擇性地增加施用對象固有口腔益菌群以修改施用對象之口腔微生物相。
有益之細菌的實例包括:緩症鏈球菌(Streptococcus mitis)、唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、小韋榮氏球菌(Veillonella parvula)、格氏鏈球菌(Streptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)和內氏放線菌(Actinomyces naeslundii)。病原性細菌的實例包括:變異鏈球菌(Streptococcus mutans)、中間普雷沃菌(Prevotella intermedia)、牙周病主要致病菌(Porphyromonas gingivalis)、有核粒梭菌(Fusobacterium nucleatum)、福賽斯坦納菌(Tannerella forsythia)、伴放線凝聚桿菌
(Aggregatibacter actinomycetemcomitans)、和遠緣鏈球菌(Streptococcus sobrinus)。
本發明已發現某些羧酸能引起益菌的生長、代謝活性和生物膜形成增加,而不會引起病原性口腔細菌的生長、代謝活性和生物膜形成增加。
因此本發明提供一種包含式I之羧酸的口腔保健組成物:
其中:R1是H,或是經取代或未經取代的烷基;且R2是H、OH或NH2;或其中該式I羧酸是反丁烯二酸或N-乙醯神經胺酸;其被用於:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的在口腔中促進對口腔健康有良性影響的細菌之生物膜形成;或(c)維持和或重建健康的口腔微生物相。
在某些實施例中,R2是H。在其他實施例中,R2是OH。在其他實施例中,R2是NH2。
在某些其中R2是NH2的實施例中,該羧酸是酸性的胺基酸。該胺基酸可為一種L-胺基酸。在某些實施例中,該酸性胺基酸是天冬胺酸或麩胺酸。在某些實施例中,該酸性胺基酸是L-天冬胺酸。在其他實施例中,該酸性胺基酸是L-麩胺酸。
在某些實施例中,R1是H。在某些實施例中,該羧酸是乙酸。
在某些實施例中,R1式一個C1-C10之經取代或未經取代的烷基。在某些實施例中,R1是一個直鏈的或分支的烷基。在某些實施例中,R1式一個環烷基。
在某些實施例中,R1是一個未經取代的烷基。在某些實施例中,R1是一個未經取代的C1-C10;C1-C6;或C1-C4烷基。在某些實施例中,R1是一個未經取代的甲基(Me)、乙基(Et)、正丙基(n-Pr)、異丙基(i-Pr)、正丁基(n-Bu)、異丁基(i-Bu)或三級丁基(t-Bu)。在某些實施例中,該羧酸是乳酸。某些實施例中,該羧酸是L-乳酸。
在某些實施例中,R1是經取代的C1-C10;C1-C6;或C1-C4烷基。在某些實施例中,R1是一個經取代的甲基(Me)、乙基(Et)、正丙基(n-Pr)、或正丁基(n-Bu)。在某些實施例中,R1是經取代的異丙基(i-Pr)、異丁基(i-Bu)或三級丁基(t-Bu)。在某些實施例中,R1經至少一個羥基取代。更多R1可經取代的實例包括(但不限於)酮基、羧酸基團、醣殘基、和酯基。
在某些實施例中,R1包含一個醣殘基。在某些實施例中,該醣殘基是一個吡喃半乳糖殘基。在某些實施例中,該吡喃半乳糖是α-D-吡喃半乳糖殘基。在某些實施例中當R1是經取代的烷基(包括但不限於一個經取代的甲基、乙基、正丙基或正丁基;或一個經取代的異丙基、異丁基或三級丁基),R1經任何以上實施例的醣殘基取代。在某些此種實施例中,R1可進而經至少一個羥基取代。在某些實施例中,R1是一個藉由糖苷鍵連接到含至少三個碳原子之碳鏈的醣殘基(亦即該羧酸具有(醣殘基-(含至少三個碳原子之碳鏈)-CHR2-COOH的結構)。該含有至少三個碳原子的碳鏈可經羥基取代。在某些實施例中,該羧酸是蜜二糖酸。
在某些實施例中,R1包含至少一個COOR3基團,其中R3是H或C1-4烷基。在某些實施例中,R3係選自甲基(Me)、乙基(Et)、正丙基(n-Pr)、異丙基(i-Pr)、正丁基(n-Bu)、異丁基(i-Bu)或三級丁基(t-Bu)。
在某些實施例中,R1是(CH2)nCOOR3,其中n是1到5的數。在某些實施例中,n是1到4的數;1到3的數;或1到2的數。在某些實施例中,n是1。在任何這些實施例中,R3可為甲基(Me)、乙基(Et)、正丙基(n-Pr)、異丙基(i-Pr)、正丁基(n-Bu)、異丁基(i-Bu)或三級丁基(t-Bu)。在某些實施例中,該羧酸是琥珀酸或L-蘋果酸。在某些實施例中,該羧酸是琥珀酸單甲酯。
在某些實施例中,R1包含至少一個C(O)COOH基。在某些實施例中,R1是(CH2)mC(O)COOH,其中m是1到4的數。在某些實施例中,m可從1到3;1到2;或是m可為1。在某些實施例中,該羧酸是α-酮基酮基戊二酸。
在某些實施例中,R1包含兩個COOH基。在某些實施例中,該羧酸是檸檬酸。
在某些實施例中,R1包含一個COOH基團和一個COOR3基團,其中R3是H或C1-4烷基。在某些實施例中,R3係選自甲基(Me)、乙基(Et)、正丙基(n-Pr)、異丙基(i-Pr)、正丁基(n-Bu)、異丁基(i-Bu)或三級丁基(t-Bu)。
在某些實施例中,該羧酸是反丁烯二酸。在某些實施例中,該羧酸是N-乙醯神經胺酸。
在某些實施例中,該羧酸係以該口腔保健組成物的重量為基準,以0.01wt%到10wt%,0.05wt%到7.5wt%,0.1wt%到5wt%,或1wt%到2.5wt%的量存在於該組成物中。
在以上任一實施例中,該羧酸可以1μmol/ml到50μmol/ml、2μmol/ml到40μmol/ml、5μmol/ml到30μmol/ml、10μmol/ml到25μmol/ml、20μmol/ml到25μmol/ml;或大約25μmol/ml、大約20μmol/ml、大約10μmol/ml、或大約5μmol/ml的量存在於該組成物中。在某些實施例中該羧酸係以22μmol/ml到30μmol/ml的含量存在於該組成物中。
在以上任一實施例中所說明的口腔保健組成物可為一種潔牙劑、牙膏、牙膠、牙粉、漱口水、口腔潤洗劑、錠劑(可溶
解或可咀嚼)、藥片、噴霧劑、口香糖或薄膜(可為完全或部分可溶的,或為不可溶的)。
在以上任一實施例中所說明的口腔保健組成物尚可包含至少一種對口腔健康具有良性影響的細菌。在這些實施例中,該組成物可被稱為共生組成物(synbiotic composition),因為其包含一種益生菌(該細菌對於口腔健康具有益的影響)和一種益生物質(該羧酸會刺激該益生菌的生長、代謝活性和/或移生)。在某些實施例中,對口腔健康具有良性影響的細菌菌種係選自緩症鏈球菌(Streptococcus mitis)、唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、小韋榮氏球菌(Veillonella parvula)、格氏鏈球菌(Streptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)和內氏放線菌(Actinomyces naeslundii)及其組合。
以上任一實施例中所說明的口腔保健組成物亦可被用於預防牙齦炎、牙周炎、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎、壞死性牙周炎和齲齒中之一種或多於一種病狀。
本發明亦提供在施用對象的口腔中選擇性促進以下項目的方法:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;或(b)相對於病原性口腔細菌的生物膜形成,選擇性的促進對口腔健康有良性影響的細菌之生物膜形成;該方法包括使施用對象的口腔與根據以上說明之任一實施例的口腔保健組成物接觸。
本發明亦提供一種維持和/或重建施用對象之健康的口腔微生物相之方法,該方法包括使施用對象的口腔與根據以上說明之任一實施例的口腔保健組成物接觸。
本發明亦提供一種預防施用對象之牙齦炎、牙周炎、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎、壞死性牙周炎和
齲齒中之一種或多於一種病狀的方法,該方法包括使施用對象的口腔與根據以上說明之任一實施例的口腔保健組成物接觸。
在以上方法中,該對象可為哺乳動物。在某些實施例中,該對象為人類。在某些實施例中,該對象為動物,例如作為陪伴的動物(例如貓或狗)。
在某些實施例中,口腔與口腔保健組成物的接觸包括用牙刷將該口腔保健組成物施用到口腔,用漱口水形式的口腔保健組成物潤洗口腔,或使用例如噴霧器將該口腔保健組成物噴灑入口腔中。
本發明亦提供以上任一實施例所述之羧酸在口腔保健組成物中的用途,用以:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的在口腔中促進對口腔健康有良性影響的細菌之生物膜形成;(c)維持和或重建施用對象之健康的口腔微生物相;或(d)預防施用對象罹患牙齦炎、牙周炎、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎、壞死性牙周炎和齲齒中之一種或多種。
在任一以上組合物、方法及用途的實施例中,在與對口腔健康具有良性影響的細菌和病原性口腔細菌培育24小時之後,相對於病原性口腔細菌的生長、代謝活性或移生,羧酸可選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生。
在任一以上組合物、方法及用途的實施例中,在與對口腔健康具有良性影響的細菌和病原性口腔細菌培育48小時之後,相對於病原性口腔細菌的生長、代謝活性或移生,羧酸可選擇性的在口腔中促進對口腔健康有良性影響之細菌的生長、代謝活性或移生。
在任一以上組合物、方法及用途的實施例中,對口腔健康具有良性影響的細菌可選自緩症鏈球菌(Streptococcus mitis)、
唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、小韋榮氏球菌(Veillonella parvula)、格氏鏈球菌(Straptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)和內氏放線菌(Actinomyces naeslundii)及其組合。另外或可選擇地,該病原性細菌可選自變異鏈球菌(Streptococcus mutans)、中間普雷沃菌(Prevotella intermedia)、牙周病主要致病菌(Porphyromonas gingivalis)、有核粒梭菌(Fusobacterium nucleatum)、福賽斯坦納菌(Tannerella forsythia)、伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans)、和遠緣鏈球菌(Streptococcus sobrinus)及其組合。
在組合物、方法和用途係關於相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的(在施用對象口腔中)促進對口腔健康有良性影響之細菌的生長、代謝活性或移生之以上任一實施例中,對口腔健康具有良性影響的細菌可選自緩症鏈球菌(Streptococcus mitis)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、小韋榮氏球菌(Veillonella parvula)、內氏放線菌(Actinomyces naeslundii)及其組合,並且在某些實施例中可選自緩症鏈球菌(Streptococcus mitis)和小韋榮氏球菌(Veillonella parvula)。另外地或可選擇地,該病原性細菌可選自變異鏈球菌(Streptococcus mutans)、中間普雷沃菌(Prevotella intermedia)、牙周病主要致病菌(Porphyromonas gingivalis)、有核粒梭菌(Fusobacterium nucleatum)、福賽斯坦納菌(Tannerella forsythia)、遠緣鏈球菌(Streptococcus sobrinus)及其組合。
在組合物、方法和用途係關於相對於病原性口腔細菌的生物膜形成,選擇性地促進對口腔健康具有良性影響之細菌的生物膜形成之以上任一實施例中,該病原性細菌可選自:變異鏈球菌(Streptococcus mutans)、中間普雷沃菌(Prevotella intermedia)、牙周病主要致病菌(Porphyromonas gingivalis)、有核粒梭菌(Fusobacterium nucleatum)、福賽斯坦納菌(Tannerella forsythia)、伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans)及其組合;並且在某些實施
例中可選自:牙周病主要致病菌(Porphyromonas gingivalis)、福賽斯坦納菌(Tannerella forsythia)和伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans)。另外地或可選擇地,該對於口腔健康具有良性影響之細菌可選自唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、格氏鏈球菌(Streptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)及其組合。
本發明的口腔保健組成物還可包含另外的成分。這些另外的成分可包括,但不限於研磨劑、稀釋劑、碳酸氫鹽、pH修飾劑、表面活性劑、泡沫調節劑、增稠劑、濕潤劑、增甜劑、風味劑、色素、抗細菌劑、抗齲齒劑、抗結石或牙垢防治劑,及其混合物。
在某些實施例中,由其(但不限於)那些實施例,其中該口腔保健組成物是牙膏,本發明的組合物上可包括一種研磨劑。可被使用的研磨劑包括矽研磨劑如平均顆粒大小高達大約20微米的沉澱或水合的矽石,如Zeodent 105和Zeodent 114(由J.M.Huber化學部門銷售,位於馬里蘭州的勒阿弗爾市(Havre de Grace),21078)或Sylodent 783(由W.R.Grace & Company公司的Davison化學部門銷售)。研磨劑如得自PQ公司的Sorbosil AC 43亦可被包含在其中。其他有用的潔牙劑之研磨劑包括氧化鋁、矽酸鋁、鍛燒氧化鋁、澎潤土或其他矽質材料、不溶的磷酸鹽,及其混合物。該研磨劑可以佔組成物重量5到30wt%,視需要佔組成物重量10到20wt%的含量存在。在某些實施例中,尤其(但不限於)那些其中口腔保健組成物是一種漱口水或口腔潤洗液的實施例中,該組成物可不含研磨劑。
在某些實施例中,本發明的口腔保健組成物包含至少一種碳酸氫鹽,其有用於例如賦予牙齒和牙齦一種「潔淨感」,因其能冒泡和釋出二氧化碳。任何口腔可接受的碳酸氫鹽均可被使用,包括而未加限制的鹼金屬碳酸氫鹽如鈉和鉀的碳酸氫鹽、碳酸氫銨及類似者。一種或多於一種另外的碳酸氫鹽視需要以佔該組成物之總重大約0.1wt%到大約50wt%,例如大約1wt%到大約20wt%的總量存在。
在某些實施例中,本發明的口腔保健組成物包括至少一種pH修飾劑。此種用劑包括酸化劑以降低pH值,鹼化劑以提高pH值,以及緩衝劑以控制pH值在所需的範圍以內。例如,可包含一種或多於一種選自酸化、鹼化和緩衝用劑的化合物以產生2到10的pH值,或在許多說明用的實施例中,2到8、3到9、4到8、5到7、6到10、7到9等的pH值。任何口腔可接受的pH修飾劑均可被使用,包括但不受限制為磷酸和磺酸及其鹽,鹼金屬氫氧化物如氫氧化鈉,碳酸鹽如碳酸鈉、碳酸氫根鹽類、倍半碳酸鹽類、硼酸鹽類、矽酸鹽類、磷酸鹽類(例如磷酸單鈉鹽、磷酸三鈉鹽)、咪唑及類似者。一種或多於一種pH修飾劑視需要以有效於維持組成物於口腔可接受之pH範圍的總量存在。
本發明的口腔保健組成物亦可包括至少一種表面活性劑。任何口腔可接受的表面活性劑,大多為陰離子的、非離子的或兩性的均可被使用。適當之陰離子表面活性劑包括但不受限制為水可溶的C8-20烷基硫酸鹽類、C8-20脂肪酸之磺酸化的單甘油酯、肌胺酸鹽類、牛磺酸類。這類和其他類別之作為說明的實例包括月桂醯基硫酸鈉、椰子單甘油酯磺酸鈉、月桂醯基肌胺酸鈉、月桂醯基羥乙基磺酸鈉、月桂醇聚醚羧酸鈉和十二烷醯基苯磺酸鈉。適當之非離子表面活性劑包括但不受限制,為泊洛沙姆(poloxamers)、聚氧乙烯山梨糖酯、脂肪醇乙氧酸酯、烷基酚乙氧酸酯、三級胺氧化物、三級膦氧化物、二烷基亞碸及類似者。適當的兩性表面活性劑包括但不受限制,為具有陰離子劑基團如羧酸鹽、硫酸鹽、磺酸鹽、磷酸鹽或膦酸鹽的C8-20脂肪族二級和三級胺類衍生物。亦可使用甜菜鹼,其適當之實例為椰子醯胺基丙基甜菜鹼。一種或多於一種表面活性劑是需要以佔該組成物之總重量大約0.01wt%到大約10wt%,例如大約0.05wt%到大約5wt%,或大約0.1wt%到大約2wt%的總量存在。
本發明的口腔保健組成物可包括至少一種泡沫調節劑,其有用於例如增加攪拌時組成物產生之泡沫量、黏稠度或穩定性。任何口腔可接受的泡沫調節劑均可被使用,包括但不被限制為聚乙二醇類(PEGs),亦以聚氧乙烯類見知。高分子量的PEGs是適當的,
包括那些具有200,000到7,000,000,例如500,000到5,000,000,或1,000,000到2,500,000的平均分子量。視需要一種或多於一種PEGs以佔該組成物總重量之大約0.1wt%到大約10wt%,例如大約0.2wt%到大約5wt%,或大約0.25wt%到大約2wt%的總量存在。
本發明之口腔保健組成物亦可包含至少一種增稠劑,其有用於例如賦予該組成物所想要的堅硬度和/或口腔感受。任何口腔可接受的增稠劑均可被使用,包括但不受限制為卡波姆(carbomers),亦以羧乙烯基聚合物、卡拉膠見知,亦以愛爾蘭青苔(Irish moss)和更尤其是-卡拉膠(iota-carrageenan)見知,纖維素的聚合物如羥乙基纖維素、羥甲基纖維素(carboxymethylcellulose,CMC)及其鹽,例如CMC鈉鹽、天然膠質如刺梧桐膠、三仙膠、阿拉伯膠和西黃耆膠(tragacanth),膠體的矽酸鎂鋁、膠體矽及類似者。一類較佳的增稠劑或凝膠化用劑包括一類丙烯酸與新戊四醇烷基醚或蔗糖烷基醚交叉連接的同聚物,或卡波姆(carbomers)。卡波姆可購自B.F.Goodrich公司,為Carbopol®產品系列。尤佳的Carbopols包括Carbopol 934、940、941、956、974P及其混合物,矽土增稠劑如DT 267(得自PPG Industries公司)亦可被使用。一種或多於一種增稠劑視需要以佔該組成物總重量大約0.01wt%到15wt%,例如大約0.1wt%到大約10wt%,或大約0.2wt%到大約5wt%的總量存在。
本發明的組成物可包含至少一種黏度修飾劑,有用於例如當攪拌液體組成物時幫助抑制成分的沉降或分離或促進再分散性。任何口腔可接受的黏度修飾劑均可被使用,包括但不限於礦物油、石油、黏土和有機修飾的黏土,矽土及類似者。一種或多於一種黏度修飾劑為視需要以佔該組成物總重量大約0.01wt%到大約10wt%,例如大約0.1wt%到大約5wt%的總量存在。
本發明的組成物亦可包含至少一種濕潤劑。任何口腔可接受的濕潤劑可被使用,包括但不受限制,為多元醇類如甘油、山梨糖醇(視需要為70wt%的水溶液)、木糖醇或低分子量的聚乙二醇類(PEGs)。大多數濕潤劑亦作用為增甜劑。一種或多於一種濕潤劑視需要以佔該組成物總重量大約1wt%到大約70wt%,例如大約1wt%
到大約50wt%、大約2wt%到大約25wt%、大約5wt%到大約15wt%的總量存在。
本發明的口腔保健組成物可包含至少一種增甜劑,其有用於例如增進該組成物的味道。一種或多於一種增甜劑視需要以強烈地視所選特殊增甜劑而定,但是典型上佔該組成物總重量的大約0.005wt%到5wt%的總量,視需要0.005wt%到0.2wt%的總量,還有視需要0.05wt%到0.1wt%的總量存在。
本發明的組成物亦可包含至少一種風味劑,其有用於例如增進該組成物的味道。可使用任何口腔可接受的天然或合成的風味劑,包括但不限於茶風味、香草、鼠尾草、墨角蘭、香芹油、綠薄荷油、肉桂油、冬青油(甲基水楊酸酯)、薄荷油、丁香油、月桂葉油、茴香油、尤佳利油、柑橘油、水果油和精油包括得自:檸檬、柑橘、萊姆、葡萄柚、杏桃、香蕉、蘋果、草莓、櫻桃、鳳梨等,得自豆類和堅果的風味如咖啡、可可、可樂、花生、杏仁等,吸附的與包覆的風味劑及類似者。同時涵蓋在本說明書之風味劑係能在口中提供香味和/或其他感官效果包括涼快或溫熱效果的成分。此種成分以作為說明的方式包括甲醇、乙酸薄荷酯、乳酸薄荷酯、樟腦、尤佳利油、桉油醇、茴香腦、丁香酚、桂皮、覆盆子酮、α-紫羅蘭酮、丙烯基二乙氧酚、百里香酚、芳樟醇、苯甲醛、肉桂醛、N-乙基-對薄荷基-3-甲醯胺、N,2,3-三甲基-2-異丙基丁醯胺、3-(1-薄荷氧基)-丙-1,2-二醇、肉桂醛甘油乙縮醛(cinnamaldehyde glycerol acetal,CGA)、薄荷酮甘油乙縮醛(menthone glycerol acetal,MGA)及類似者。一種或多於一種風味劑視需要以佔該組成物總重量之大約0.01wt%到大約5wt%,例如大約0.03wt%到大約2.5wt%,視需要大約0.05wt%到大約1.5wt%,還有是需要大約0.1wt%到大約0.3wt%的總量存在。
本發明的組成物可包含至少一種著色劑。本說明書的著色劑包括色素、染料、色澱和賦予特殊光澤或反射性的用劑如珠光劑。任何口腔可接受的著色劑均可被使用,包括但不受限於滑石、雲母、碳酸鎂、碳酸鈣、矽酸鎂、矽酸鋁鎂、矽土、二氧化鈦、氧化鋅、紅色、黃色、褐色和黑色的氧化鐵、亞鐵氰化鐵銨、錳紫、群青、
鈦酸處理之雲母、氯氧化鉍及類似者。一種或多於一種著色劑視需要以佔該組成物總重量大約0.001wt%到大約20wt%,例如大約0.01wt%到大約10wt%,或大約0.1wt%到大約5wt%的總量存在。
本發明的組成物亦可包含一種抗菌劑或保存劑,如雙氯苯雙胍己烷、三氯沙、四級銨化合物(例如氯化烷基二甲基苄基銨)或對羥基苯甲酸類如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯。一種或多於一種抗菌劑或保存劑視需要以佔該組成物之總重量大約0.01wt%到大約0.5wt%,視需要大約0.05wt%到大約0.1wt%的總量存在於該組成物中。
該口腔保健組成物亦可包含一種氟離子來源。氟離子來源包括但不限於:氟化亞錫、氟化鈉、氟化鉀、單氟磷酸鉀、單氟磷酸鈉、單氟磷酸銨、氟矽酸鈉、氟矽酸銨,胺的氟化物如奧拉氟(olaflur)(N'-十八烷醯基三亞甲基二胺-N,N,N'-三(2-乙醇)-二氫氟化物)、氟化銨及其組合。在某些實施例中該氟離子來源包括氟化亞錫、氟化鈉、胺的氟化物、單氟磷酸鈉、及其混合物。在某些實施例中,本發明的口腔保健組成物亦包含一種氟離子來源或提供氟的成分,其量足以供應大約50到大約5000ppm氟離子,例如大約100到大約1000ppm、大約200到大約500ppm或大約250ppm氟離子。氟離子來源可以大約0.001wt%到大約10wt%,例如大約0.003wt%到大約5wt%、0.01wt%到大約1wt%或大約0.05wt%的量添加到該本發明的組成物中。然而,吾人必須瞭解提供適當氟離子量之氟化物鹽類的重量顯然會依該鹽類中對應離子的重量而異,熟習本技藝者會很容易地測定出此量。一種較佳的氟化物鹽是氟化鈉。
本發明的組成物可包含唾液刺激劑,其有用於例如舒緩口乾。任何口腔可接受的唾液刺激劑均可被使用。視需要一種或多於一種唾液刺激劑以其刺激唾液的有效總量存在。
根據本發明的組成物可包含抗敏感劑,例如鉀鹽如硝酸鉀、碳酸氫鉀、氯化鉀、檸檬酸鉀,以及草酸鉀;辣椒素(capsaicin)、丁香酚(eugenol)、鍶鹽、氯化物鹽類及其組合。此種用劑
可以有效量添加,例如佔該組成物總重量大約1wt%到大約20wt%的量添加,視所選擇的用劑而定。
本發明的組成物尚可包含一種抗氧化劑。任何口腔可接受的抗氧化劑均可使用,包括丁基化的羥基羥茴香醚(butylated hydroxyanisole,BHA)、丁基化的羥基甲苯(butylated hydroxytoluene,BHT)、維生素A、類胡蘿蔔素、維生素E、黃酮類、多酚類、草本抗氧化劑、葉綠素、褪黑素及其混合物。
本發明的組成物可另外視需要包含如以下提供之防治牙石垢(抗結石)的用劑。有用於本發明之牙垢防治劑中包括特定用劑的鹽類,包括鹼金屬鹽和銨鹽。該用劑包括:磷酸鹽和多磷酸鹽、多胺基丙磺酸(polyaminopropanesulfonic acid,AMPS)、聚烯烴磺酸鹽類、聚烯烴磷酸鹽類、二膦酸鹽類如氮雜環烷-2,2-二膦酸鹽類(例如,氮雜環庚烷-2,2-二膦酸)、N-甲基氮雜環戊烷-2,3-二膦酸、乙烷-1-羥基-1,1-二膦酸(ethane-1-hydroxy-1,1-diphosphonic acid,EHDP)和乙烷-1-胺基-1,1-二膦酸鹽。有用的無機磷酸鹽和多磷酸鹽包括磷酸單鈉鹽、磷酸二鈉鹽和磷酸三鈉鹽、三多磷酸鈉、四多磷酸鹽、三偏磷酸鈉、六偏磷酸鈉及其混合物。其他有用的牙垢防治劑包括多羧酸鹽聚合物和聚乙烯基甲基醚/順丁烯二酸酐(polyvinyl methyl ether/maleic anhydride,PVM/MA)共聚物,如GANTREZ®。
實例1
吾人研究羧酸類:琥珀酸、L-乳酸、琥珀酸單甲酯、L-蘋果酸、檸檬酸、蜜二糖酸、α-酮基戊二酸、乙酸和L-天冬胺酸存在下各種口腔益菌和病原性的口腔細菌之代謝活性。
被試驗的口腔益菌為緩症鏈球菌(Streptococcus mitis)、唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、格氏鏈球菌(Streptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)和內氏放線菌(Actinomyces naeslundii)和小韋榮氏球菌
(Veillonella parvula)。被試驗的病原性口腔細菌是變異鏈球菌(Streptococcus mutans)、中間普雷沃菌(Prevotella intermedia)、牙周病主要致病菌(Porphyromonas gingivalis)、有核粒梭菌(Fusobacterium nucleatum)、福賽斯坦納菌(Tannerella forsythia)、伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans)和遠緣鏈球菌(Streptococcus sobrinus)。
能夠增加至少一種以上益菌之代謝活性而不會或僅些微增加病原性細菌之代謝活性的基質被認為是幫助益菌生長的基質。
於以上提到的酸存在下24小時和48小時後,透過一台用於微生物細胞之高處理量表現型微陣列系統(phenotype microarray system,PM)(Biolog Inc.出品)檢測被試驗的細菌之代謝活性大小。每一PM可包含高達95種可作用為細菌基質的相異生化學化合物(例如有機酸),其以及一個不含基質的陰性對照組。使用微陣列盤,其中每盤的不同孔洞均經由(製造商Biolog Inc)預先裝載不同的待試驗有機酸。利用分開的微陣列盤試驗每一菌種。因此,用各種有機酸在每一特殊的盤上試驗單一菌種。該微陣列是根據氧化還原技術,利用細胞呼吸作為共通的報信者。活性細胞呼吸會造成四唑染料減少並且形成很濃的顏色-例如,當使用四唑染料「Biolog氧化還原染劑混合物D(Biolog Redox Dye Mix D)」時,顏色會從透明無色轉變成當燃料被還原的紫色。此種顏色變化的觀察指示出哪種基質能增進細胞的代謝活性與健康。
從血液瓊脂培養皿上收集每一菌種(在37℃厭氧狀態下培育48小時)並且轉移到IF-0基礎接種液(Biolog Inc.出品),其為一種營養缺乏的培養基。將所得到的細胞懸浮液調整到在波長492nm用BioRad SmartSpec 3000光度計偵測為穿透度42%(相對於沒有菌種的基礎接種液之穿透度)(該調整是藉由添加更多接種液或更多細菌直到達成42%穿透度來實行的)。此種懸浮液之1:5緩衝液是藉著將3mL之穿透度42%的細胞懸浮液與15mL之接種液混合而製備的(該接種液是藉著將11.6mL無菌水、62.5mL IF-0基礎接種液與0.9mL四唑染料
(Biolog氧化還原染劑混合物D)混合所形成,使得最終的細胞密度用BioRad SmartSpec 3000光度計偵測等於85%穿透度。對每一受試的酸,該微陣列盤(得自供應商Biolog Inc.),在個別孔槽中已有呈粉末形式的酸在其中)被直接以100μL/每孔槽之此種85%穿透度的細胞懸浮液進行接種。
將所有培養皿培育在37℃厭氧的氛圍中。顏色變化是在波長492nm下用光譜儀(Thermo Scientific Multiskan Ascent)在24小時和48小時,利用相同的盤皿在兩個不同的時點測量的。對於每一受試的細菌,亦使用個別對照組,該對照組是一個含有某種細菌(細胞懸浮液)但不含任何羧酸的盤皿孔槽。在24小時和48小時之後連續震盪下於一台多重掃描微皿讀取機上,在492nm的波長下對每一細菌/有機酸組合和對其個別之每一對照組(亦即含有某種細菌但不含羧酸)利用微皿讀取機測量其在24小時和48小時之合成培養基的光密度(OD)。對於每種細菌,在24小時和48小時得到的OD值除以對個別對照組在24小時和48小時得到的OD值(個別地),使得對照組之數值為1。因此對於某一細菌與羧酸的組合之大於1的數值係指示細菌在24小時或48小時的代謝活性增加大於觀察到之對照組之活性增加。
對於每一細菌與羧酸組合進行三次實驗,每一重複試驗是在不同天進行的(因此提供三個生物複本)。對照組試驗亦如上進行三次。顯示的數值是對於每一細菌與羧酸組合在24小時和48小時所得到之三個單一數值的平均值(如以上詳細說明過的)。結果顯示在以下表1到4中:
在以上的數據中,數值2被當作閾值,高於此值有機酸會引起細菌的代謝活性顯著增加。此值經挑選以排除低度刺激代謝物和避免假陽性結果。.
從以上數據可見,琥珀酸、L-乳酸、琥珀酸單甲酯和L-蘋果酸在24小時展現益生質作用且琥珀酸、琥珀酸單甲酯、檸檬酸、蜜二糖酸、α-酮基戊二酸、乙酸和L-天冬胺酸在48小時展現益生質作用。不受限於任何理論地,吾人相信能在48小時展現益升值效果的基質長期使用可對於口腔提供有益的影響。
因為L-乳酸被益菌代謝要比病原性的細菌快(由以上數據組中的數值2顯示益菌在24小時可達到但是病原性細菌卻無法達到),L-乳酸的存在被預期能引起益菌在很短的時間規模裡抑制病原性細菌的生長,因此維持健康的口腔微生物相。因為L-乳酸被益菌代謝要比病原性的細菌快,這種有機酸在病原性細菌能開始使用它之前就被益菌消耗/代謝掉了(且因此從環境中被取走)。不受限於理論,吾人相信當益菌和病原性細菌的混合物存在時(如在口腔之中),在48小時看見之L-乳酸對病原性細菌的刺激效果可能會被徹底破壞,因為這種有機酸基質已經被益菌代謝且因此無法被病原菌獲得使用。因此,益菌的生長/代謝活性/移生是在病原性細菌之前就被刺激,則益菌可倍增,並且在病原性細菌有機會生長/倍增之前即對病原性細菌行使抑制作用。
實例2
吾人研究在羧酸類例如L-天冬胺酸和琥珀酸存在下,各種口腔益菌和病原性口腔細菌的生長程度。
被試驗的口腔益菌為緩症鏈球菌(Streptococcus mitis)、唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、格氏鏈球菌(Streptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)和內氏放線菌(Actinomyces naeslundii)和小韋榮氏球菌(Veillonella parvula)。被試驗的病原性口腔細菌為變異鏈球菌(Streptococcus mutans)、中間普雷沃菌(Prevotella intermedia)、牙周病主要致病菌(Porphyromonas gingivalis)、有核粒梭菌(Fusobacterium nucleatum)、福賽斯坦納菌(Tannerella forsythia)、伴放線凝聚桿菌(Aggregatibacter actinomycetemcomitans)和遠緣鏈球菌(Streptococcus sobrinus)。
能夠增加至少一種以上有益細菌之生長(或最大生長密度或生長程度)而不增加或僅僅微量增加病原細菌生長(或最大生長密度)的基質被認為是益生質化合物。
受試的細菌的生長程度對挑選的羧酸(L-天冬胺酸、琥珀酸)之反應是藉著在營養豐富的基質(腦心浸潤的肉汁(brain heart infusion broth,BHI),Oxoid公司出品)中經48小時建立生長曲線來進行研究。對於粘放線菌(A.viscosus)、小韋榮氏球菌(V.parvula)、有核粒梭菌(F.nucleatum)、牙周病主要致病菌(P.gingivalis)、中間普雷沃菌(P.intermedia)、福賽斯坦納菌(T.forsythia)、內氏放線菌(Actinomyces naeslundii)及生痰嗜二氧化碳噬纖細菌(C.sputigena)將個別細菌從血液瓊脂培養皿轉移到BHI中並且在37℃厭氧氛圍下培育至隔夜來製備後指數生長相的液體培養物,並且對於唾液鏈球菌(S.salivarius)、血鏈球菌(S.sanguinis)、緩症鏈球菌(S.mitis)、伴放線凝聚桿菌(A.actinomycetemcomitans)、變異鏈球菌(S.mutans)、遠緣鏈球菌(Streptococcus sobrinus)和格氏鏈球菌(S.gordonii)則使其在5%CO2環境中。將隔夜的培養物倒入BHI並藉著在波長600nm測量光密度(OD600)(使用BioRad SmartSpec 3000光度
計)將濃度調整到1×107CFU/ml(每毫升菌落形成單位)。對於每一菌株,將200μl細菌懸浮液添加到含有20μl之個別羧酸的96-孔盤皿。將羧酸的最終濃度設在5、10、20和25μmol/ml。對每種受試的細菌,亦使用不含羧酸的個別對照組。將盤皿如先前說明的方式培育。
對於每種細菌/羧酸的組合,及其每一個別對照組(亦即某細菌在營養充分不含羧酸之培養基中),在0小時、24小時和48小時測量波長630nm的光密度(OD630)(使用Thermo Scientific Multiskan Ascent酶標儀)。此外,亦在0小時和9小時之間每小時測量細菌/羧酸組合在5%CO2的環境下之OD630。對於每一細菌/羧酸組合超過48小時期間所得到的最大OD值除以對於個別對照組超過48小時期間所得到的最大OD值,使得對照組具有1的值。因此大於1之某一細菌與羧酸的組合數值即指示細菌超過48小時生長的程度要大於對照組的細菌超過48小時生長的程度。
對每一細菌與羧酸組合和對每一對照組,本實驗是在相異的三天裡實行的(因此提供三個生物複本)並且在每一天該實驗是以四次重複進行的(因此提供四個技術複本)。對於每一天和對於每一組合,對四個技術複本所得到數值的平均(平均值)(如以上詳細說明者)進行計算以產生每一組合於每一天的單值。該數值顯示在以下表5到6之中,其係從每一細菌與羧酸組合所得到的三個單值的平均(平均值)。結果顯示在以下表5到6:
在以上數據中,1.25的值被當作閾值,高於此值則相較於對照組羧酸會顯著引起細菌生長增加。此值係經過挑選以排除低度刺激的代謝物和避免假陽性結果。
從以上數據可見,L-天冬胺酸在10和20μmol/ml展現益生質效果,而琥珀酸則在20和25μmol/ml的濃度展現益生質效果。
實例3
吾人亦以L-天冬胺酸和琥珀酸為例,羧酸對於各種口腔益菌和病原性口腔細菌之生物膜生長的影響進行探究。
能夠增加至少一種以上的益菌生物膜量增加,而不會或僅僅極少量增加病原性細菌之生物膜的基質被認為是益生質化合物。
藉著在營養豐富的培養基(腦心浸潤的肉汁(BHI),Oxoid公司出品)中設定生物膜的生長檢驗48小時,來研究受試驗細菌對所選羧酸(L-天冬胺酸和琥珀酸)反應之生物膜形成的增加。對於粘放線菌(A.viscosus)、小韋榮氏球菌(V.parvula)、有核粒梭菌(F.nucleatum)、牙周病主要致病菌(P.gingivalis)、中間普雷沃菌(P.intermedia)、福賽斯坦納菌(T.forsythia)、內氏放線菌(Actinomyces naeslundii),及生痰嗜二氧化碳噬纖細菌(C.sputigena)將個別細菌從血液瓊脂培養皿轉移到BHI中並且在37℃厭氧氛圍下培育至隔夜來製備後指數生長相的液體培養物,並且對於唾液鏈球菌(S.salivarius)、血鏈球菌(S.sanguinis)、緩症鏈球菌(S.mitis)、伴放線凝聚桿菌(A.actinomycetemcomitans)、變異鏈球菌(S.mutans)、和格氏鏈球菌(S.
gordonii)則使其在5%CO2環境中。將隔夜的培養物倒入BHI並藉著在波長600nm測量光密度(OD600)(使用BioRad SmartSpec 3000光度計)將濃度調整到1×107CFU/ml(每毫升菌落形成單位)。對於每一菌株,將200μl細菌懸浮液添加到含有20μl之個別羧酸的96-孔盤皿。將羧酸的最終濃度設在5、10、20和25μmol/ml。對每種受試的細菌,亦使用不含羧酸的個別對照組。將盤皿如先前說明的方式培育。另外,對每種試驗細菌增添一項用以校正背景染色的背景對照組。該背景對照組含有受試的細菌和0.03wt%的雙氯苯雙胍己烷作為抗菌劑。將盤皿如先前說明的方式培育。48小時之後移除盤皿之孔洞中的上澄液。將孔洞用1×100μL磷酸鹽緩衝液(sphosphate buffered saline,PBS)沖洗兩次,用體積比96%的乙醇(體積比96%的水溶液)固定20分鐘並用1wt%的龍膽紫(1wt%的水溶液)將留在孔洞底部的生物膜染色。用體積比5%的乙酸(體積比5%的水溶液)溶解結合的染料。利用多重掃描微皿讀取機(Thermo Scientific公司出品)藉由測量波長630nm的吸光值進行染色生物膜的定量。
對於每一細菌/羧酸的組合,在扣除掉背景對照組的OD值之後將48小時的OD值除以對個別對照組所獲得的OD值,使得對照組的數值為1。大於1之某一細菌與羧酸的組合數值即指示經48小時之生物膜生長要大於對照組經48小時的生物膜生長。
該實驗是在三個不同天裡進行的(因此提供三個生物複本),並且對於每一細菌與羧酸組合和每一對照組而言,每天該實驗均重複進行四次(因此提供四個技術複本)。對於每一天和對於每一組合,對四個技術複本所得到數值的平均(平均值)(如以上詳細說明者)進行計算以產生每一組合於每一天的單值。該數值顯示在以下表7到表8之中,其為對於每一細菌與羧酸組合所得三個單值的平均(平均值)。該結果顯示在以下表7到表8之中:
在以上數據中,數值1.6被當作閾值,高於此值有機酸會造成細菌生物膜生長較對照組顯著增加。此值係經挑選以排除低刺激性的代謝物並且避免假陽性結果。
吾人可從以上數據發現L-天冬胺酸和琥珀酸在25μmol/ml均展現益生質的效果。
Claims (7)
- 一種琥珀酸單甲酯於製造口腔保健組成物之用途,其用於:(a)相對於病原性口腔細菌的生長、代謝活性或移生,選擇性的在口腔中,促進對口腔健康有良性影響之細菌的生長、代謝活性或移生;(b)相對於病原性口腔細菌的生物膜形成,選擇性的在口腔中促進對口腔健康有良性影響的細菌之生物膜形成;或(c)維持及/或重建健康的口腔微生物相。
- 根據申請專利範圍第1項之用途,其中以該口腔保健組成物重量為基準,該羧酸以0.01重量%到10重量%含量存在於該組成物中。
- 根據申請專利範圍第1或2項之用途,其中該羧酸係以5μmol/ml到30μmol/ml的含量存在於該組成物中。
- 根據申請專利範圍第1或2項之用途,其中該組成物為潔牙劑、牙膏、牙膠、牙粉、漱口水、口腔潤洗劑、錠劑、藥片、噴霧劑、口香糖或薄膜。
- 根據申請專利範圍第1或2項之用途,其中該組成物更包含至少一對口腔健康具有良性影響的菌種。
- 根據申請專利範圍第5項的用途,其中該對口腔健康具有良性影響的菌種係選自緩症鏈球菌(Streptococcus mitis)、唾液鏈球菌(Streptococcus salivarius)、口腔鏈球菌(Streptococcus oralis)、粘放線菌(Actinomyces viscosus)、小韋榮氏球菌(Veillonella parvula)、格氏鏈球菌(Streptococcus gordonii)、生痰嗜二氧化碳噬纖細菌(Capnocytophaga sputigena)和內氏放線菌(Actinomyces naeslundii)及其組合。
- 根據申請專利範圍第1或2項之用途,其用於預防牙齦炎、牙周炎、植體周圍炎、植體周圍粘膜炎、壞死性牙齦炎、壞死性牙周炎和齲齒中之一種或多種。
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