TWI425948B - Compositions for the inhibition or killing of Porphyromonas gingivalis and their use for the alleviation or treatment of periodontal disease and other diseases - Google Patents
Compositions for the inhibition or killing of Porphyromonas gingivalis and their use for the alleviation or treatment of periodontal disease and other diseases Download PDFInfo
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- TWI425948B TWI425948B TW101102379A TW101102379A TWI425948B TW I425948 B TWI425948 B TW I425948B TW 101102379 A TW101102379 A TW 101102379A TW 101102379 A TW101102379 A TW 101102379A TW I425948 B TWI425948 B TW I425948B
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- extract
- antrodia camphorata
- gingivalis
- killing
- porphyromonas gingivalis
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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Description
本發明係關於一種用於抑制或殺除牙齦卟啉單胞菌(Porphyromonas gingivalis
)之組成物。本發明亦關於一種用於製造抑制或殺除牙齦卟啉單胞菌之醫藥品的用途。本發明亦關於一種用於製造減輕或治療牙齦卟啉單胞菌所衍生的疾病之醫藥品的用途。
根據牙醫師公會全國聯合會統計資料，台灣地區成年人罹患牙周病比例高達9成，其中牙周細菌(periodontal bacteria)感染牙齦組織或牙齒的齒槽骨係造成牙周病的主要原因。
目前已知的主要致病之牙周細菌主要有伴放線菌放線桿菌(Actinobacillus actinomycetemcomitans
,Aa)、牙齦卟啉單胞菌(Porphyromonas gingivalis
,Pg)、具核梭桿菌(Fusobacterium nucleatum
)及福氏擬桿菌(Bacteroides forsythus
,Bf)。而口腔中唾液成分之醣蛋白(glycoprotein)會在牙齒表面形成薄膜，使前述的牙周細菌易附著於牙齒表面，進而形成牙菌斑(plaque)，而牙菌斑再與唾液中的鈣質結合，逐漸變硬而形成牙結石(dental calculus)。且牙周細菌表面的菌毛(fimbriae)會分泌分解蛋白質的酵素而溶解牙齦細胞，並入侵到牙齦內部，進而破壞牙齦組織及牙齒之骨質，並造成骨質疏鬆。
其中牙齦卟啉單胞菌係一種生長於厭氧(anaerobic)環境的革蘭氏陰性菌(gram-negative bacteria)，不僅常見於口腔，更可生長於上腸胃道(upper gastrointestinal tract)、呼吸道(respiratory tract)及結腸(colon)等。近年有研究指出，牙齦卟啉單胞菌會誘導基質金屬蛋白脢(matrix metalloproteinases,MMPs)加速發炎反應，且細菌細胞壁表面之脂多醣(lipopolysaccharide,LPS)亦會引發宿主過度的免疫反應，亦會誘發介白素(Interleukin)增生，而使類風濕性關節炎(rheumatoid arthritis)惡化，且牙齦卟啉單胞菌甚至會隨著血流循環至全身血管，進而導致心肌梗塞(myocardial infarction)、動脈硬化(arteriosclerosis)、血栓閉塞性血管炎(thromboangiitis Obliterans,TAO)、細菌性肺炎(bacterial pneumonia)、糖尿病(diabetes)等疾病。
目前治療牙周病可分為機械式及化學性兩種，其中機械式的控制，包括牙刷、牙線之使用、超音波潔牙及牙根面平整術；但在手術後或特殊情況下，可配合有化學性療效的牙膏及漱口水，以輔助控制牙周病。現有市售的牙膏或漱口水大多含有酒精或是氯己定(chlorhexidine)以減少並抑制口腔內細菌的滋生，其中高濃度酒精類漱口水會破壞口腔及舌頭黏膜，增加病毒或致癌物滲透率，而增加口腔癌的風險；其中氯己定雖有較好的抑菌效果，但容易使牙齒及舌頭染色，且具有味道不佳、暫時性味覺障礙、暫時性上皮脫落及牙結石堆積增加等副作用。
除了以上西醫的治療方式之外，中醫治療牙周病主要係服用中草藥以去除體內溼熱合併健脾胃之方法，以緩減牙齦組織發炎。常被國人使用之中草藥之一的牛樟芝(Antrodia camphorata)，其含有三萜類化合物(triterpenoids)、多醣體(polysaccharides)、超氧岐化酶(superoxide dismutase,SOD)及腺苷(adenosine)等活性成份，近來研究顯示，以上活性成份具有抗腫瘤、抗發炎、抗高血壓、降血糖及降膽固醇等功效，然而未有技術顯示牛樟芝可供用於口腔衛生之保健使用，亦未有技術顯示其具有殺除特殊厭氧菌或半厭氧菌之功效。
有鑑於現有技術的前述缺失，本發明之目的在於提供一種用於抑制或殺除牙齦卟啉單胞菌(Porphyromonas gingivalis
)之組成物及其應用，其組成物含有有效抑制或殺除牙齦卟啉單胞菌之劑量的牛樟芝粉末或其萃取物以及其可接受的載劑。相較於現有技術的抗生素，本發明之牛樟芝粉末或其萃取物以較低的濃度即可作為抑制牙齦卟啉單胞菌之用途，且牛樟芝萃取物係來自天然植物，並不會有上述酒精或氯己定之副作用，而具有較高的安全性。
為達到上述之目的，本發明提供一種用於抑制或殺除牙齦卟啉單胞菌(Porphyromonas gingivalis
)之組成物，其組成物含有有效抑制或殺除牙齦卟啉單胞菌之劑量的牛樟芝粉末或其萃取物以及其可接受的載劑，其中該牛樟芝萃取物係由牛樟芝以水、有機溶劑或其等之組合所萃取而得。
依據本發明，如此處所使用的用語「有效抑制或殺除牙齦卟啉單胞菌之生長劑量」意指能夠使得牙齦卟啉單胞菌之生長減緩、停止，甚致死亡，其如本發明所例示者，有效抑制牙齦卟啉單胞菌可透過活體外牙齦卟啉單胞菌之最低抑菌濃度予以測定而得；有效殺除牙齦卟啉單胞菌，可透過活體外牙齦卟啉單胞菌之最低殺菌濃度予以測定而得。
依據本發明，牛樟芝係包括任何形式培養，例如固態培養、液態培養或其混合方式，所取得的牛樟芝產物，只要其具有如本案所述之有效抑制或殺除牙齦卟啉單胞菌之活性即適用於本發明，例如，但不限於：牛樟芝之菌絲體、子實體。
較佳的，所述之牛樟芝萃取物，係由牛樟芝子實體以水或有機溶劑萃取而得，其中有機溶劑包括，但不限於醇類、酯類、烷類或鹵烷類。
較佳的，所述之牛樟芝萃取物濃度係由牛樟芝子實體以不同濃度之乙醇水溶液萃取而得。
依據本發明，用語「不同濃度之乙醇水溶液」如此處所使用的係指以20%、50%或95%濃度之乙醇水溶液。
較佳的，所述之牛樟芝萃取物係由牛樟芝子實體以濃度95%乙醇水溶液萃取。
依據本發明之「可接受的載劑」如此處所使用的係指若醫藥組合物為口服型式，則載劑係能保護該醫藥組合物在尚未到達作用位置前不受消化系統的分解，而失去效用，和/或能夠促進醫藥組合物的釋放以及效果。
較佳的，所述之有效抑制或殺除牙齦卟啉單胞菌之牛樟芝萃取物之劑量是介於1微克/毫升(μg/ml)與16微克/毫升之間。更佳的，所述之有效抑制或殺除牙齦卟啉單胞菌之牛樟芝萃取物之劑量是介於2 μg/ml與4 μg/ml之間。
另一方面，本發明亦提供一種用於製造抑制或殺除牙齦卟啉單胞菌之醫藥品的用途，其醫藥品含有有效抑制或殺除牙齦卟啉單胞菌之劑量的牛樟芝或其萃取物。
較佳的，所述之有效抑制或殺除牙齦卟啉單胞菌之牛樟芝萃取物是以介於1 μg/ml至16 μg/ml的劑量予以投藥。更佳的，所述之有效抑制或殺除牙齦卟啉單胞菌之牛樟芝萃取物是以介於2 μg/ml至4 μg/ml之間的劑量予以投藥。
又另一方面，本發明提供一種用於抑制或殺除牙齦卟啉單胞菌之組成物用於製造減輕或治療牙齦卟啉單胞菌所衍生的疾病的用途，其中牙齦卟啉單胞菌所衍生的疾病包括牙周病、心血管疾病及免疫疾病。
較佳的，所述之牙周病包括，但不限於牙周炎(paradentitis)及牙齦炎(gingivitis)。
較佳的，所述之心血管疾病包括，但不限於心肌梗塞(myocardial infarction)、感染性心內膜炎(infective endocarditis)、動脈硬化(arteriosclerosis)及血栓閉塞性血管炎(thromboangiitis obliterans,TAO)。
較佳的，所述之免疫疾病包括，但不限於類風濕性關節炎rheumatoid arthritis、紅斑性狼瘡(lupus erythematosus)、牛皮癬(psoriasis)及發炎性腸炎(inflammatory bowel disease)。
依據本發明，用語「減輕或治療」係指該醫藥組成物可治癒或舒緩所述的疾病或病徵。
依據本發明的醫藥組成物，其被製造成，包括但不限於：食品、清潔用品、飲品，其具體實施例包括：牙膏及漱口水等。
本發明之牛樟芝萃取物經證實具有有效抑制或殺除牙齦卟啉單胞菌生長的功效，且相較於現有技術的抗生素具有更低的有效抑制濃度，是以能作為一種新穎的抗牙齦卟啉單胞菌之組成物，藉以減輕或治療因牙齦卟啉單胞菌所衍生的疾病衍生，包括牙周病、心血管疾病或免疫疾病。由於牛樟芝萃取物係源自本土植物牛樟芝之子實體，因此易於取得，且其可藉由本發明所述的方法純化、分離，並無化學合成物之副作用問題，因而可容易被應用於各種產業，尤其如保健食品、飲品及生活用品等應用。
本發明將由下列的實施例做為進一步說明，這些實施例並不限制本發明前面所揭示的內容。熟習本發明之技藝者，可以做些許之改良與修飾，但不脫離本發明知範疇。
實施例
材料及方法
1.化學藥品與試劑
氯己定二葡萄糖酸鹽(Chlorhexidine digluconate,CHX)購自於Alfa aesar公司；鹽酸半胱氨酸(Cysteine HCl)購自於sigma公司；氯化血红素(Hemin)購自於Fluka公司；腦心浸劑培養基(brain heart infusion agar,BHI agar)購自於BD公司；腦心浸劑培養液(brain heart infusion broth,BHI broth)購自於BD公司；酵母萃取液(yeast extract,YE)購自BD公司；維生素K1(Vitamin K1)購自sigma公司；去纖維綿羊血(defibrinated sheep blood)購自波仕特生物科技股份有限公司)；二甲基亞碸(dimethyl sulfoxide,DMSO)購自sigma公司；95%乙醇(95% EtOH)購自sigma公司。
2.補充腦心浸劑培養基(supplemented brain heart infusion agar,sBHI agar)及補充腦心浸劑培養液(supplemented brain heart infusion broth,sBHI broth)之製作將5.2公克(g)的腦心浸劑培養基及0.5g的酵母萃取液加於水中使體積為100毫升(ml)，滅菌後置於50℃，並加入5%去纖維綿羊血，即為補充腦心浸劑培養基；將3.7 g的腦心浸劑培養液及0.5 g的酵母萃取液加於水中使體積為100 ml，滅菌後冷卻至室溫後，加入0.05 g的鹽酸半胱氨酸、1 ml的氯化血红素溶液(hemin solution)及20微升(μl)的維生素K1，此即為補充腦心浸劑培養液。
3.製備牛樟芝萃取物
取10 g野生牛樟芝(Antrodia camphorata
)(南投縣信義鄉，台灣)之乾燥粉末加入100 ml之95%乙醇，於29℃下萃取48小時後，經由真空旋轉濃縮及真空冷凍乾燥後，置於-80℃下備用，係為牛樟芝95%乙醇萃取物。其中，前述牛樟芝之乾燥粉末是藉由下列步驟所製得：提供野生牛樟芝子實體；乾燥該牛樟芝子實體；以及研磨該經乾燥的牛樟芝子實體，以取得牛樟芝之乾燥粉末。
4.菌種材料
牙齦卟啉單胞菌(Porphyromonas gingivalis
)購自食品工業研究所，其寄存編號為BCRC14417，於冷凍管解凍後，使用補充腦心浸劑培養液活化並於37℃厭氧(80% N2
,10% H2
,10% CO2
)條件下培養24小時至48小時。
5.最低抑菌濃度測定(minimal inhibitory concentration,MIC)將牙齦卟啉單胞菌於補充腦心浸劑培養液中，以37℃厭氧(80% N2
,10% H2
,10% CO2
)條件下培養24小時至48小時，稀釋至每毫升1×108
菌落形成單位(CFU/ml)後[透光率%(transmittance,T%)=25%透光密度600(optical density 600,OD600)]，取195 μl置入96孔盤(96 well microplates)，並加入5 μl之牛樟芝95%乙醇萃取物或氯己定二葡萄糖酸鹽(以下簡稱氯己定)做為正對照組(positive control)，該牛樟芝95%乙醇萃取物之最終濃度分別為每毫升1、2、4、8、16微克(μg/ml)，並以最終濃度2.5%(v/v)的二甲基亞碸作為控制組。於37℃厭氧(80% N2
,10% H2
,10% CO2
)條件下培養24小時，經微量讀測儀(microplate reader)之波長600奈米(nm)測量，並以吸收值(absorbance,Abs)≦0.5之濃度作為最低抑菌濃度(Mi-Sun Kanget a1
.,2008,The journal of Microbiology
,744-750)。
6.最低殺菌濃度測定(minimum bactericidal concentrations,MBC)
將牙齦卟啉單胞菌於補充腦心浸劑培養液中，以37℃厭氧(80% N2
,10% H2
,10% CO2
)條件下培養48小時，稀釋至1×105
CFU/ml，取195 μl置入96孔盤加入5 μl之牛樟芝95%乙醇萃取物或氯己定做為正對照組，其最終濃度分別為1、2、4、8或16 μg/ml，再於37℃厭氧(80% N2
,10% H2
,10% CO2
)條件下培養48小時，並取10 μl小劑量(aliquot)之牛樟芝95%乙醇萃取物或氯己定於含有5%去纖維綿羊血之補充腦心浸劑培養基上，以已滅菌之三角型玻棒輕輕塗抹菌液至乾，使菌液均勻塗佈於5%去纖維綿羊血之補充腦心浸劑培養基上，再於37℃厭氧(80% N2
,10% H2
,10% CO2
)條件下培養5天(day)，以無菌落生長之濃度作為最低殺菌濃度(Myrella Lessio Castroet al
.,2009,Bioorganic &Medicinal Chemistry
,17: 5332-5335)。
7.數據統計
試驗結果均以平均值±標準偏差(mean±SD)表示，每次試驗採三重複，重複三次獨立試驗，數據之統計分析採用T檢定(Student’s t-test)之統計方法進行差異性分析，當p
<0.01代表與對照組有統計上之顯著差異。
實施例1：最低抑菌濃度測定(minimal inhibitory concentration,MIC)
本實施例是利用如「材料及方法」中所述的最低抑菌濃度測定來評估牛樟芝95%乙醇萃取物之最低抑菌濃度。
結果如圖1所示，顯示牛樟芝95%乙醇萃取物之濃度在4 μg/ml以下，其吸收值高於0.5；如圖2所示，正對照之氯己定之濃度在4 μg/ml以下，其吸收值高於0.5，因此牛樟芝95%乙醇萃取物之最低抑菌濃度為4 μg/ml，而正對照組氯己定之最低抑菌濃度為4 μg/ml。
實施例2：最低殺菌濃度測定(minimum bactericidal concentrations,MBC)
本實施例是利用如「材料及方法」中所述的最低殺菌濃度測定來評估牛樟芝95%乙醇萃取物之最低殺菌濃度。
結果如圖3所示，顯示牛樟芝95%乙醇萃取物之濃度於2 μg/ml以上，其含有5%去纖維綿羊血之補充腦心浸劑培養基並無菌落生成；氯己定之濃度於4 μg/ml以上，該含有5%去纖維綿羊血之補充腦心浸劑培養基無菌落生成。
如表1所示，牛樟芝95%乙醇萃取物之最低殺菌濃度為2 μg/ml，而作為正對照組之氯己定之最低殺菌濃度為4 μg/ml，顯示牛樟芝95%乙醇萃取物有相較於現有技術用於抑制或殺除牙齦卟啉單胞菌效果更佳。
圖1係牛樟芝95%乙醇萃取物於不同濃度(1、2、4、8及16 μg/ml)抑制牙齦卟啉單胞菌，所測得之抑菌濃度之折線圖。
圖2係氯己定於不同濃度(1、2、4、8及16 μg/ml)抑制牙齦卟啉單胞菌，所測得之抑菌濃度之折線圖。
圖3係牛樟芝95%乙醇萃取物及氯己定於不同濃度(2、4 μg/ml)抑制牙齦卟啉單胞菌，所測得之最低殺菌濃度之柱狀圖。
Claims (7)
- 一種含有牛樟芝萃取物以及其可接受的載劑之組成物用於製造抑制或殺除牙齦卟啉單胞菌之醫藥品的用途，其醫藥品含有有效抑制或殺除牙齦卟啉單胞菌之劑量的牛樟芝或其萃取物，其組合物中該牛樟芝萃取物係由牛樟芝以水、有機溶劑或其等之組合所萃取而得。
- 如請求項1所述之用途，其中有效抑制或殺除牙齦卟啉單胞菌之牛樟芝萃取物是以介於1μg/ml至16μg/ml之間的劑量予以投藥。
- 如請求項1所述之用途，其中有效抑制或殺除牙齦卟啉單胞菌之牛樟芝萃取物是以介於2μg/ml至4μg/ml之間的劑量予以投藥。
- 一種含有牛樟芝萃取物以及其可接受的載劑之組成物用於有效抑制或殺除牙齦卟啉單胞菌之組成物用於製造減輕或治療牙齦卟啉單胞菌所衍生的疾病之醫藥品的用途，其中牙齦卟啉單胞菌所衍生的疾病包括牙周病、心血管疾病及免疫疾病，其組合物中該牛樟芝萃取物係由牛樟芝以水、有機溶劑或其等之組合所萃取而得。
- 如請求項4所述之用途，其中牙周病包含有牙周炎(paradentitis)或牙齦炎(gingivitis)。
- 如請求項4所述之用途，其中心血管疾病包含有心肌梗塞(myocardial infarction)、感染性心內膜炎(infective endocarditis)、動脈硬化(artcriosclerosis)或血栓閉塞性血管炎(thromboangiitis obliterans,TAO)。
- 如請求項4所述之用途，其中免疫疾病包含有類風濕 性關節炎(rheumatoid arthritis)、紅斑性狼瘡(lupus erythematosus)、牛皮癬(psoriasis)或發炎性腸炎(inflammatory bowel disease)。
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| JPH0759496B2 (ja) * | 1986-03-25 | 1995-06-28 | ロ−ト製薬株式会社 | 歯周病治療剤 |
| US5990100A (en) * | 1998-03-24 | 1999-11-23 | Panda Pharmaceuticals, L.L.C. | Composition and method for treatment of psoriasis |
| KR20020055546A (ko) * | 2000-12-28 | 2002-07-09 | 박정시 | 애완동식물 관리 시스템 및 관리 방법 |
| NZ545692A (en) * | 2003-09-03 | 2009-02-28 | Kowa Co | PPAR-activating compound and pharmaceutical composition containing same |
| ATE513823T1 (de) * | 2004-08-17 | 2011-07-15 | Simpson Biotech Co Ltd | Mischung und verbindungen von mycelien von antrodia camphorata und deren verwendung |
| TWI394572B (zh) * | 2007-06-12 | 2013-05-01 | Golden Biotechnology Corp | Application of Cynanchum aurantii Cyclohexenone Compounds in the Preparation of Drugs for the Treatment of Autoimmune Diseases |
-
2012
- 2012-01-20 TW TW101102379A patent/TWI425948B/zh active
- 2012-03-05 US US13/411,704 patent/US9480722B2/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201200144A (en) * | 2009-11-26 | 2012-01-01 | Univ Nat Taiwan | An anti-cancer active substance from Antrodia camphorata, method for preparing the same and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US20130189296A1 (en) | 2013-07-25 |
| US9480722B2 (en) | 2016-11-01 |
| TW201330858A (zh) | 2013-08-01 |
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