CN1047517C - 口用卫生组合物 - Google Patents
口用卫生组合物 Download PDFInfo
- Publication number
- CN1047517C CN1047517C CN93121598A CN93121598A CN1047517C CN 1047517 C CN1047517 C CN 1047517C CN 93121598 A CN93121598 A CN 93121598A CN 93121598 A CN93121598 A CN 93121598A CN 1047517 C CN1047517 C CN 1047517C
- Authority
- CN
- China
- Prior art keywords
- compositions
- nisin
- oral cavity
- antimicrobial
- anion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000000203 mixture Substances 0.000 title claims abstract description 86
- 108010053775 Nisin Proteins 0.000 claims abstract description 36
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- 239000004309 nisin Substances 0.000 claims abstract description 36
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- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 claims description 32
- 229960003500 triclosan Drugs 0.000 claims description 31
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 28
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 27
- -1 anion silicon dioxide Chemical class 0.000 claims description 27
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- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 10
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
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- 230000000843 anti-fungal effect Effects 0.000 description 8
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- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 8
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- CUQCMXFWIMOWRP-UHFFFAOYSA-N phenyl biguanide Chemical compound NC(N)=NC(N)=NC1=CC=CC=C1 CUQCMXFWIMOWRP-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
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- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- 239000000429 sodium aluminium silicate Substances 0.000 description 1
- 235000012217 sodium aluminium silicate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000019983 sodium metaphosphate Nutrition 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- CKVCFYYFFUHCDP-UHFFFAOYSA-M sodium;phosphoric acid;fluoride Chemical compound [F-].[Na+].OP(O)(O)=O CKVCFYYFFUHCDP-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910002029 synthetic silica gel Inorganic materials 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960000323 triclabendazole Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- LRXTYHSAJDENHV-UHFFFAOYSA-H zinc phosphate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LRXTYHSAJDENHV-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Birds (AREA)
- Pharmacology & Pharmacy (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
含有乳酸链球菌肽，抗微生物剂和牙科可接受的赋形剂或载体的口用养护组合物用来治疗或预防牙斑，牙周疾病以及口内真菌浸染。
Description
本发明涉及口用卫生组合物，特别是漱口剂和牙粉，它们具有改良的抗一组包括细菌和真菌的口腔重要致病微生物的活性。
口腔致病细菌与许多口腔疾病有关，这些疾病包括牙斑，牙龈炎和牙周病。另外，致病真菌如念珠菌也能存活于口腔内而引起病态如需要治疗的鹅口疮。
过去推荐用作口腔抗菌剂的试剂包括阳离子类，如双氯苯双胍己烷，双胍啶，6—氨基—1，3—双(β—乙己基)—5—甲基六氢嘧啶和十六烷基比啶鎓氯化物，以及非阳离子类，如二氯苯氧氯酚。这些抗菌剂中的一部分作为抗真菌剂也是有效的。
近来，有人提出多肽抗菌素乳酸链球菌肽(Morck Index，11th edn，entry 6431)可用于口腔卫生。乳酸链球菌肽是含有一个特定氨基酸羊毛硫氨酸的lanthocin，是由细菌乳链球菌的不同菌株天然产生的。它也是发现于低浓度牛奶和乳酪中的一种天然存在的防腐剂。最近乳酸链链球菌肽被FDA认可为一种直接使用的食品成分。在Advances in Applied Microbiology27(1981)，85-123中可找到一篇有关乳酸链球菌肽特性的综述。最近已制备出乳酸链球菌肽的纯化形式，可由Applied Mic-robiology Inc得到，商品名为Ambicin N。
在WO93/11738和WO89/12399中公开了乳酸链球菌肽的口腔保护用途。前者公开了适当的牙粉配方，后者公开了口清洁剂形式的广谱消毒剂组合物，其中乳酸链球菌肽与非杀菌剂如表面活性剂或螯合剂相混合，扩大了该组合物的活性范围。
在很多例子中，单个的抗微生物剂对口腔内发现的较宽范围的病原微生物不具有明显的广谱活性。因为存在的两种抗微生剂活性的相互拮抗，所以不同抗微生物试剂的组合并不总是成功的。
现在我们惊奇地发现乳酸链球菌肽可以与一种抗微生物剂有效地组合，而不破坏乳酸链球菌肽或这种抗微生物剂的活性。
因此，本发明提供了一种口用卫生组合物，它含有有效抗细菌用量的乳酸链球菌肽，有效抗微生物用量的一种抗微生物剂以及口腔内可接受的载体或赋形剂。
合适的抗微生物剂可具有抗细菌或抗真菌的活性，或者具有抗细菌和抗真菌的综合活性。
用于本发明组合物的合适抗微生物剂包括阳离子抗微生物剂和非阳离子抗微生物剂，以及其它多肽抗菌素(细菌素)和抗真菌剂。因而，在优选实施方案中，本发明提供了一种口用卫生组合物，它包括有效抗细菌用量的乳酸链球菌肽，有效抗微生物用量的一种抗微生物剂，该抗微生物剂包括一种阳离子抗微生物剂，一种非阳离子抗微生物剂，一种其它(非乳酸链球菌肽)的多肽抗菌素(细菌素)或一种抗真菌剂，以及一种口腔内可接受的载体或赋形剂。
本发明组合物具有一种较宽范围的抗微生物活性。如乳酸链球菌肽具有有限的抗念珠菌种活性，而在乳酸链球菌肽存在下，象双氯苯双胍己烷，十六烷基吡啶鎓氯化物或二氯苯氧氯酚可保持其抗念珠菌的活性。类似的，乳酸链球菌肽具有较弱的抗P gingivalis的活性，却发现混合短杆菌素(tyrothricin)具有较好的抗该菌的活性。
在本发明组合物中可适当地使用纯化形态的乳酸链球菌肽，如由Applied Microbiology Inc.，170，53rd Strecd，Brooklyn，New York，NY 11232，USA出售的产品，商品名为Ambicin N。
本发明的口用卫生组合物所含的乳酸链球菌肽可适当为本组合物重量的0.001至5.0％，优选0.005至2.0％，最好为0.02至1.0％。在另一个可选择的方案中，所需的乳酸链球菌肽的含量是能在口腔中抑制靶微生物的足够用量。抑制靶微生物的乳酸链球菌肽的有效含量大约为0.99ppm。
用于本发明口用卫生组合物的合适阳离子抗微生物试剂包括：
(i)季铵化合物，例如该化合物的四价氮上的一个或两个取代基具有8至20个，优选10至18个碳原子，且最好为一个烷基，其中可任意插有酰胺，酯、氧，硫，或杂环，而其余的取代基具有较少数目的碳原子，例如1至7个碳原子，且优选为烷基，如甲基、乙基或苄基。这类化合物的例子包括benzalkonium氯化物，十二烷基三甲基铵氯化物，苄基二甲基十八烷铵氯化物，十六烷基三甲基铵溴化物，苄乙氧基铵氯化物(二异丁基苯氧乙氧乙基二甲基苄基铵氯化物)和甲基苄乙氧铵氯化物；
(ii)吡啶鎓和异喹啉鎓化合物，包括十六烷基吡啶鎓氯化物，十六烷基吡啶鎓氯化物和烷基异喹啉鎓溴化物；
(iii)嘧啶衍生物例如氨己嘧啶(5—氨基—1，3—双(2—乙己基)—5—甲基六氢嘧啶)；
(iv)脒衍生物，如六嘧啶羟乙磺酸盐(4，4′)—二脒基—α,ω—二苯氧基己烷羟乙基磺酸盐)；
(v)双吡啶衍生物，如辛烯啶Octenidine(N，N′[1，10—癸二基二—1(4H)—吡啶基—4—亚基]—双(1—辛胺二盐酸盐)；和
(vi)双胍类，包括：
(a)单双胍，如P—氯苄基双胍，和N′—(4—氯苄基)—N″—(2，4—二氯—苄基)双胍；
(b)具有下列通式的双双胍类化合物：A(X)zNRC(＝NH)NHC(＝NH)NH(CH2)nNHC(＝NH)NHC(＝NH)NR′(X′)z′A′其中：A和A′可以相同或不同，分别表示可任意被(C1-4)烷基，(C1-4)烷氧基，硝基和卤原子取代的苯基，(C1-12)烷基或(C4-12)脂环基团；X和X′可相同也可不同，每个表示(C1-3)亚烷基；R和R′可相同也可不同，分别表示氢原子，(C1-12)烷基，或芳基(C1-6)烷基；Z和Z′可相同也可不同，每个表示0或1；n是2至12的整数；和聚亚甲基链(CH2)n中可任意插有氧原子或硫原子或芳香的(如苯基或萘基)环，以及其牙科可接受的酸加成盐；特别是双氯苯双胍己烷，双胍啶和其盐如双氯苯双胍己烷二葡糖酸盐和双氯苯双胍己烷乙酸盐；和
(c)聚(双胍)如聚亚己基双胍盐酸盐。
优选的阳离子抗微生物剂包括如式(I)的双胍类，如双氯苯双胍己烷或双胍啶，或其口腔内可接受的酸加成盐，十六烷基吡啶鎓氯化物，氨己嘧啶柠檬酸盐和氯化苄乙氧铵。
一般地，阳离子抗微生物剂的含量范围是口用卫生组合物重量的0.005至10％，优选0.005至5％，更优选0.005至2.5％。
合适的水几乎不溶的非阳离子抗微生物剂包括，如卤化羟基二苯醚类和硫醚类；苯酚和二苯酚类化合物，包括卤化水扬酰苯胺，N—碳酰苯胺；苯甲酸酯包括2—和4—羟基苯甲酸酯和N—碳酰苯胺类，特别是卤化的N—碳酰苯胺。
卤化的羟基二苯醚的例子包括，如3，3′—二溴—5，5′—二氯—2，2′—二羟基二苯醚和2，4，4′—三氯—2′—羟基二苯醚(triclosan)，其中2，4，4′—三氯—2′—羟基二苯醚是最佳的。卤化的羟基二苯硫醚的例子包括双(2—羟基—3，5—二氯苯基)硫醚，和双(2—羟基—5—氯苯基)硫醚。苯酚类化合物的例子包括，如2—苯基苯酚；4—氯苯酚；4—氯—3—甲基苯酚；4—氯—3，5—二甲基苯酚；2，4—二氯—3，5—二甲基苯酚；5—甲基—2—戊基苯酚；4—异丙基—3—甲基苯酚；5—氯—2—羟基二苯基甲烷；4′，5—二溴水扬酰苯胺；3，4′，5—三溴水扬酰苯胺；2，3，3′，5—四氯水扬酰苯胺；3，3′，4，5′—四氯—水扬酰苯胺；3，5—二溴—3′—三氟甲基水扬酰苯胺和5—正辛酰基—3′—三氟甲基水扬酰苯胺。二苯酚化合物的例子包括，如5，5′—二氯—2，2′—二羟基二苯基甲烷；2，2′—二羟基—3，5，6，3′，5′，6′—六氯二苯基甲烷；2，2′—亚甲基—双(3，4，6—三氯苯酚)；2，2′—亚甲基—双(4—氯苯酚)；和2，2′—亚甲基—双(4—氯—6—溴苯酚)。苯甲酸酯的例子包括羟基苯甲酸酯，特别是甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、己酯，庚酯和苄酯及水扬酸苯酯。N—碳酰苯胺类的例子包括，如，3，4，4′—三氯—N—碳酰苯胺，3—三氟甲基—4，4′—二氯—N—碳酰苯胺，和3，3′，4—三氯—N—碳酰苯胺。最好的水不溶非阳离子抗微生物剂为2，4，4′—三氯—2′—羟基二苯醚。
一般地，水不溶非阳离子抗微生物剂的含量范围是该组合物重量的0.005至2％，优选是0.005至1％，更优选为0.005至0.3％。
用作抗微生物剂的合适多肽抗菌素(细菌素)包括短杆菌肽(Gramicidin)(Merck Index，11th edn.，entry 4438)和混合短杆菌素(MerckIndex，11th edn.，entry 9745)。应当理解为混合短杆菌素是通常含有大约10—20％的短杆菌肽和40—60％短杆菌酪肽的多肽抗菌素混合物。这类其它多肽抗菌剂合适的含量范围是该组合物重量的0.001至5.0％，优选0.005至2.0％，最好为0.02至1.0％。在另一种可选择的方案中，所需多肽抗菌剂的含量是口腔中抑制靶微生物的足够用量。
用于本发明组合物中的合适抗真菌剂包括已知的咪唑和三唑试剂，如双氯苯咪唑，三氯苯咪唑，或其它的已知试剂，如制真菌素。这类抗真菌剂的合适含量为该组合物总重量的0.001至1.0％，优选0.01至0.5％，更优选0.05至0.3％。这里所用的抗真菌剂的合适剂量范围是本领域中所公知的。如双氯苯咪唑是以每剂125至250mg的口服剂量使用的。
优选的抗微生物剂包括双氯苯双胍己烷和双胍啶及其盐，特别是双氯苯双胍己烷二葡糖酸盐和二氯苯双胍己烷乙酸盐，十六烷基吡啶鎓氯化物，氨己嘧啶柠檬酸盐，二氯苯氧氯酚，水扬酸苯酯，短杆菌肽和短杆菌素，最好是双氯苯双胍己烷二葡糖酸盐，二氯苯氧氯酚和十六烷基吡啶鎓氯化物。
抗微生物剂如双氯苯双胍己烷，十六烷基吡啶鎓氯化物和二氯苯氧氯酚具有抗细菌和真菌的活性。在很多情况中，已发现抗真菌活性所需的抗微生物剂浓度要比抗细菌所需的要低。如，在大约8.15ppm浓度下，十六烷基吡啶鎓氯化物能杀死在实施例226中所示的所有微生物。见表1。比较而言，仅需约1.39ppm的十六烷基吡啶鎓氯化物就能抑制念珠菌微生物。同样对于双氯苯双胍己烷和2，4，4′—三氯—2′—羟基苯醚，抑制所有的目标口腔微生物所需的浓度分别是约8.46ppm和约7.65ppm，而抑制念珠菌的浓度分别是1.71ppm和约1ppm，所以，如果所包括的抗微生物剂主要具有抗念珠菌活性时，就用低浓度的这类抗微生物剂组合到本发明组合物中以补充乳酸链球菌肽活性范围的间隙。
因此，另一方面本发明提供了一种口用卫生组合物，它包括有效抗菌用量的乳酸链球菌肽，优选纯化形式的Ambicin N，和有效抗念珠菌用量的抗微生物试剂，优选十六烷基吡啶鎓氯化物，双氯苯双胍己烷或二氯苯氧氯酚。
本发明口用卫生组合物可被制成本领域中常用的任一剂型；如，漱口剂，洁牙剂，包括牙膏和牙粉，液体牙膏，凝胶剂，片剂，锭剂或口香糖。为制备这些剂型，可据本领域熟练技术人员公知的原理选择口腔可接受的载体或赋形剂。这类组份包括有表面活性剂，增稠剂，润湿剂和磨擦剂，当需要时，还可任选口用保护组合物中常包括的其他附加物，这类组份应与乳酸链球菌肽和抗微生物剂相溶。因此，过去我们已发现(WO93/11738，Smithkline Beecham)多肽抗菌素如乳酸链球菌肽，短杆菌肽和混合短杆菌素与经常用于口用保护组合物的阴离子表面活性剂如月桂基硫酸钠和N—甲基—N—Cocyl月桂酸钠不相溶。最好避免用这类阴离子表面活性剂，而使用非离子、阳离子或两性表面活性剂替代。
同样，本领域熟练技术人员认识到由于阳离子抗微生物剂与常用于口腔保护组合物制剂中的阳离子类物质，特别是阳离子表面活性剂和至少与双氯苯双胍己烷，阳离子增稠剂的不相溶性，阳离子抗微生物剂如双氯苯双胍己烷以及在较低程度上，十六烷基吡啶鎓氯化物在制剂上存在问题。这些最好避免。另外，对于洁牙剂来说，注意需要加入选择的合适磨擦剂(如下文描述)。
这里所用的涉及制剂或成份选择参考的术语“相溶”是指该组分具有基本上不损害抗细菌剂乳酸链球菌肽或另外一种抗微生物剂的活性。含有该组分与不含该组分相比，它们的活性适当为不低于40％，优选不低于50％，最好不低于60％。这很容易用生物分析法进行检测，例如对于那些试剂，如MicrococcusLuteus NCTC 8166(对于2，4，4′—三氯—2′羟基苯醚)的抗微生物灵敏性，可使用常规区带扩散分析方法。
根据本发明，例如组合物中所用的合适表面活性剂包括非离子，阳离子和两性表面活性剂或其混合物。
合适的非离子表面活性剂包括，例如，聚乙氧基山梨糖醇酯，特别是聚乙氧基山梨糖醇单酯，如PEG(40)二异硬脂酸脱水山梨糖酯，和由ICI以商品名“Tween“市售的产品；环氧乙烷和环氧丙烷的缩聚物(Poloxamers)，如由BASF—Wyandotte以商品名“Pluronic”市售的产品；丙二醇缩合物；聚乙氧基氢化蓖麻油，如Cremophors；和脂肪酸脱水山梨糖酯。
合适的两性表面活性剂包括，如长链咪唑啉衍生物，象由Miranol以商品名“Miranol C2M”市售的产品；长链烷基甜菜碱，如由Albright＋Wilson以商品名‘Empigen BB’市售的产品，以及长链烷基酰氨烷基甜菜碱，如椰子酰氨丙基甜菜碱，及它们的混合物。
合适的阳离子表面活性剂包括乙基—N—Cocoyl—L—精氨酸酯的D，L—2—吡咯烷酮—5—羧酸盐，由Ajinomoto Co.Inc.出售的商品CAE；和椰子酰氨丙基PG dimonium氯化物磷酸盐和月桂酰胺丙基PG dimonium氯化物磷酸盐，可由Mona Cor-poration得到商品名分别为Monaquat PTC和Monaquat PTL的商品。
该表面活性剂的有益含量是洁牙剂总重量的0.005至20％，优选0.1至10％，更优选为0.1至5％。
合适的增稠剂例如有非离子增稠剂如(C1-6)烷基纤维素醚，如甲基纤维素；羟基(C1-6)烷基纤维素醚，如羟乙基纤维素和羟丙基纤维素；(C2-6)烯化氧改性的(C1-6)烷基纤维素醚，如羟丙基甲基纤维素；以及其混合物。尽管在含有二双胍试剂如双氯苯双胍己烷或双胍啶组合物中应避免使用其它增稠剂如天然和合成胶或胶类物象Irish Moss，黄蓄树胶；羧甲基纤维素钠，聚乙烯吡咯烷酮，淀粉和稠化硅石，但它们仍可适用于本发明的许多组合物。尽管也可以用羧甲基纤维素，但适当的增稠剂已减少了阴离子基团数，如羧基。优选的增稠剂是甲基纤维素的衍生物，如羟乙基纤维素或羟丙基甲基纤维素。
增稠剂的最好含量为组合物重量的0.01至30％，优选0.1至15％，更优选1至5％。
用于本发明组合物的合适润湿剂例如有甘油，山梨糖醇，丙二醇或聚乙二醇或其混合物。润湿剂含量为洁牙剂重量的5至70％，优选5至30％，更优选10至30％。当非离子增稠剂是羟丙基甲基纤维素时，润湿剂合适含量高达洁牙剂重量的30％。
用于本发明洁牙组合物的合适磨擦剂有碳酸钙，磷酸钙，焦磷酸钙，不溶性偏磷酸钠，硅铝酸钠，氧化铝，水合氧化铝，正磷酸锌，塑性颗粒和硅石，其中硅石是优选的磨擦剂。
合适的硅石有天然非晶形硅石，象硅藻土，和合成的无定形硅石，如沉淀硅石和硅胶，包括二氧化硅干凝胶。合适的二氧化硅干凝胶在US 3538230中有描述。沉淀硅石的合适级别是20至300，优选20至100m2/g的BET表面积，2至50μ优选5至30μ的平均附聚物大小。
合适的沉淀硅石和二氧化硅干凝胶是分别由Degussa和WR Grace Corporation Davison Chemical Division以商品名Sident和Syloblanc出售的商品。
该硅石最好是“低阴离子”硅石。这里使用的术语“低阴离子”硅石是指在生产中小心控制下，把通常在生成过程中所产生的阴离子杂质如硫酸钠和硅酸钠降低到最小值。“低阴离子”的硅石合适的阴离子杂质重量为1％以下优选0.5％以下，最好为0.25％以下。
合适的“低阴离子”硅石在EP0368130(Proctor和Gamble)，EP0315503和EP0396459(Rhone Poulenc)和WO90/05113(J.M.Huber Corp)中有所描述。或者，用去离子水洗涤各级带有离子杂质的商品硅石使其达到适当的要求。测定洗涤后水的导电率来监控这种洗涤效果。洗涤后水的导电率适当降低到200μSiemens/cm以下。合适的“低阴离子”硅石包括由Rhone-Poulenc得到的RP93级。
当附加抗细菌剂是双缩二胍衍生物如二氯苯二胍己烷时，并且磨擦剂为硅石衍生物时，优选的合适硅石是“低阴离子”型。
组合物适当地含有5至80％，优选10至60％的磨擦剂(按重量计)。
可适合含有乳酸链球菌肽和双氯苯双胍己烷组合物的双氯苯双胍己烷组合物的合适洁牙剂在EP0364245-A和EP0422803—A(Beecham Group plc)和EP0368130(Proctor和Gamble)中有所描述。可适合含有乳酸链球菌肽和十六烷基吡啶鎓氯化物的十六烷基吡啶鎓氯化物的组合物的合适洁牙剂型在US 5176901(Smithkllne Beecham Corporation)中有所描述。
最好的一方面是，本发明洁牙组合物含有乳酸链球菌肽，优选Ambicin N形式；选自十六烷基吡啶鎓氯化物，一种双氯苯双胍己烷盐或2，4，4′—三氯—2′—羟基苯醚中，优选双氯苯双胍己烷盐或2，4，4′—三氯—2′—羟基苯醚的一种抗微生物剂；一种非离子表面活性剂，如环氧乙烷和环氧丙烷缩聚物；一种非离子增稠剂，如羟丙基甲基纤维素；一种润湿剂如，甘油；和一种磨擦剂如“低阴离子”硅石或碳酸钙，可任意与正单磷酸二钙组合，且包括一种碱土金属盐象氯化钙。
优选的另一方面是，本发明洁牙组合物含有一种非离子表面活性剂如环氧乙烷和环氧丙烷的缩聚物，一种增稠剂如羧甲基纤维素钠，可任与稠化硅石提前混合，一种润湿剂如山梨糖醇，可任与甘油提前混合和一种磨擦剂如“低阴离子”硅石。
适宜的漱口剂具有包括水或含水乙醇并可任含一种如甘油或丙二醇类的液体的含水基质。还可含有一种表面活性剂来提高该组合物的敏感性。漱口组合物可制成“容易使用”的形式，如浓缩液，在使用前被使用者迅速稀释；或者固体形式如片剂或小药囊，在使用前被使用者迅速溶解。用木糖醇和/或山梨糖醇为主要成分制备成合适的片剂。小药囊和片剂可被配制为一种一旦溶解不起泡的漱口剂，或混合合适的起泡对如碳酸钠/碳酸氢钠和柠檬酸配制成一种起泡漱口剂。
本发明组合物可有用地含有氟离子源，以提供抗龋活性。已发现氟离子源与乳酸链球菌肽能够相溶。对乳酸链球菌肽与抗微生物制剂组合的合适氟源决定于所选择的特定的抗微生物剂。每个合适的抗微生物剂的相溶性或不相溶性在本领域中是被公知的和被确证的。因此需要时，合适的氟离子源包括金属氟盐，如碱金属氟盐象氟化钠，氟化胺盐；碱金属单氟磷酸盐如一氟代磷酸钠和一氟代磷酸胺盐。如果存在合适的氟离子源时，它的浓度为50至3500ppm，优选100至2500ppm的氟离子。
除润湿剂外，本发明组合物还可以含有其它液体如水，优选去离子水。
根据WO89/12399(Public Health Research Institute of theCity of New York)的说明书，本发明组合物可以有用地含有口腔可接受的螯合剂如EDTA或柠檬酸或其碱金属盐，如柠檬酸氢二钠。含有乳酸链球菌肽的合适浓度为0.1至300μg/ml，且含有螯合剂的合适浓度为0.1至20mM。
乳酸链球菌中含有特定的氨基酸羊毛硫氨酸，它通常被认为是两个丙氨酸单位与一共用的硫原子成键生成一个硫醚键。这种键合比较脆弱，容易发生蛋白水解，导致失活。这被认为是由口用卫生组合物中的某些成分，特别是某些成分存在的杂质产生的自由基引起的。我们发现一些象Tweens级别的非离子表面活性剂和一些级别的某些润湿剂可能会产生这类问题。因此优选使用较纯级别的制剂组分。另外，或作为一种比较方案，作为游离基清除剂的一种竞争基质如蛋氨酸可有用地包括在该组合物中。
口腔可接受的赋型剂或载体也可包括其他任选组份象矫味剂，甜味剂，如糖精钠；染料，增白剂如二氧化钛，防腐剂，抗敏剂，如锶和钾盐，抗垢剂如焦磷酸四碱金属盐和二碱金属盐。应当理解为在每个例子中如果含有任意组分，它们与乳酸链球菌肽和抗微生物剂都是相溶的。还应当理解为辅助成分如锶是以与其它成分象氟离子源相溶的方式组合的。
本发明组合物具有口腔可接受的且基本上不损害乳酸链球菌肽抗细菌活性范围内的PH值。PH的合适范围是4到9.5，优选4到6.5，更优选4到5.5，最佳为5到5.5。
本发明组合物可用常用方法制备，包括以适当相对量和任何方便的顺序混合各组份，最后，如果需要的话，把PH调至所需值。
本发明的组合物目的在于用来预防和/或治疗口腔疾病。特别是本发明组合物能有效抗牙斑细菌，所以这类组合物可用于抗牙斑的治疗。因而，另一方面，本发明还提供了一种减少或防止牙斑生成的方法，该方法包括向需要治疗的患者施用有效抗牙斑用量的本发明组合物。本发明组合物也用于预言或治疗牙周病，包括牙龈炎。因此本发明也提供了预防或治疗牙周病的方法。前文所定义的某些本发明组合物也用于治疗口腔真菌感染。因此本发明也提供了一种治疗或预防口腔真菌感染的方法。
现参考下面实施例对本发明加以详细说明。实施例1—牙膏Ambicin N 0.50％二氯苯氧氯酚 0.2甘油 22.00羟丙基甲基纤维素 3.40二氧化钛 1.00糖精钠 0.25Poloxamer(Pluronic F108) 2.00矫味剂 1.00硅石(RP93) 16.00去离子水 足量另外实施例可用0.1或0.3％二氯苯氧氯酚制备。实施例2—牙膏Ambicin N 0.50％双氯苯双胍己烷二葡糖酸盐 0.50甘油 22.00羟丙基甲基纤维素 3.00二氧化钛 1.00糖精钠 0.10Poloxamer(Pluronic F108) 2.00矫味剂 1.00Talin 0.02硅石(RP93) 16.00去离子水 足量其它实施例可用0.05％或1.0％双氯双胍己烷二葡糖酸盐制备。实施例3—牙膏Ambicin N 0.50％十六烷基吡啶鎓氯化物 0.5甘油 22.00羟丙基甲基纤维素 3.40二氧化钛 1.00糖精钠 0.10Poloxamer(Pluronic F108) 2.00矫味剂 1.00Talin 0.02硅石(RP93) 16.00去离子水 足量另外实施例可用0.05％或1.0％十六烷基吡啶鎓氯化物制备。实施例4—牙膏Ambicin N 0.050％二氯苯氧氯酚 0.30山梨糖醇(70％水溶液) 20.00甘油 15.00羟甲基纤维素钠 1.20氟化钠 0.23硅石(RP93) 16.00稠化硅石(Sident 22) 5.00糖精钠 0.30Poloxamer(Pluronic F108) 2.00去离子水 足量其它实施例用0.1或0.2％二氯苯氧氯酚制备。实施例5—牙膏Ambicin N 0.05％十六烷基吡啶鎓氯化物 1.0山梨糖醇(70％水溶液) 20.00甘油 15.00羟甲基纤维素钠 1.20氟化钠 0.23硅石(RP93) 16.00稠化硅石(Sident 22) 5.00糖精钠 0.30Poloxamer(Pluronic F108) 2.00去离子水 足量其它实施例可用0.05或0.5％十六烷基吡啶鎓氯化物制备。实施例6—牙膏Ambicin N 0.05％二氯苯氧氯酚 0.20甘油 20.00Methocel K15 Premium 0.20Methocel K100 Premium 3.20二氧化钛 1.00糖精钠 0.33Poloxamer(20％Pluronic F108水溶液) 10.00氟化钠 0.221矫味剂 1.00硅石(RP93) 16.00去离子水 足量其它实施例可用羧甲基纤维素钠(1.20％)代替Methocel K15和Methocel K100制备。另外，二氯苯氧氯酚的含量为0.1％或0.3％。实施例7—牙膏Ambicin N 0.05％双氯苯双胍己烷二葡糖酸盐 1.0甘油 22.00Methocel K15 Premium 0.20Methocel K100 Premium 3.20二氧化钛 1.00糖精钠(30％水溶液) 0.33Poloxamer(20％Plurcnic F108水溶液) 10.00氟化钠 0.22矫味剂 1.00Talin(5％水溶液) 0.40硅石(RP93) 16.00去离子水 足量其它实施例可用羧甲基纤维素钠(1.20％)代替Methocel K15和Methocel K100制备。另外，双氯双胍己烷二葡糖酸盐的浓度可以为1.0％或0.05％。实施例8—牙膏Ambicin N 0.05％十六烷基吡啶鎓氯化物 1.0甘油 22.00Methocel K15 Premium 0.20Methocel K100 Premium 3.20二氧化钛 1.00糖精钠(30％水溶液) 0.33Poloxamer(20％Pluronic F108水溶液) 10.00氟化钠 0.221矫味剂 1.00Talin(5％水溶液) 0.40硅石(RP93) 16.00去离子水 足量其它实施例可用羧甲基纤维素钠(1.20％)代替Methocel K15和Methocel K100制备。另外，十六烷基吡啶鎓氯化物的含量可为0.05％或0.5％。实施例9—漱口剂Ambicin N 0.030％二氯苯氧氯酚 0.020甘油 5.000调味剂 0.075乙醇(96％) 15.00可溶糖精 0.010氟化钠 0.023颜料 0.100丙二醇 15.00去离子水 足量另外的实施例可用0.01％或0.03％二氯苯氧氯酚制备。实施例10—漱口剂Ambicin N 0.030％二氯苯氧氯酚 0.03甘油 30.00矫味剂 0.075乙醇(96％) 15.00Cremophor RH60 0.60可溶性糖精 0.005氟化钠 0.023颜料 0.10去离子水 足量另外可选择的配方可用丙二醇代替Cremophor RH60，并且二氯苯氧氯酚含量可以为0.005，0.01％或0.02％。实施例11—漱口剂Ambicin N 0.030％双氯苯双胍己烷二葡糖酸盐 0.01甘油 5.000矫味剂 0.075乙醇(96％) 5.00可溶性糖精 0.010氟化钠 0.023颜料 0.100Cremophor RH60 0.1去离子水 足量其它实施例可用0.2％的Cremophor RH60制备，另外，双氯苯双胍己烷二葡糖酸盐含量为0.05％，0.1％或0.2％。实施例12—漱口剂Ambicin N 0.030％十六烷基吡啶鎓氯化物 0.01％甘油 5.000矫味剂 0.075乙醇(96％) 5.00可溶性糖精 0.0001氟化钠 0.023颜料 0.001Cremophor RH60 0.1EDTA 0.004去离子水 足量其它实施例可用0.2％的Cremophor RH60制备。另外，Cremophor RH60不用或被非离子表面活性剂如Tween20或Triton X100(0.2％)代替。其它实施例可用0.05，0.1或0.2％十六烷基吡啶鎓氯化物制备。实施例13—漱口剂Ambicin N 0.030％二氯苯氧氯酚 0.005柠檬酸氢二钠 0.263乙醇(96％) 15.00丙二醇 15.00甘油 30.00去离子水 足量其它实施例可用0.01％，0.02％或0.03％的二氯苯氧氯酚制备。实施例14—漱口剂Ambicin N 0.030％双氯苯双胍己烷二葡糖酸盐 0.005柠檬酸氢二钠 0.263去离子水 足量其它实施例可用0.05％，0.1％或0.2％的双氯苯双胍己烷二葡糖酸盐制备。实施例15—漱口剂Ambicin N 0.030％十六烷基吡啶鎓氯化物 0.01柠檬酸氢二钠 0.263去离子水 足量其它实施例可用0.05，0.1或0.2％十六烷基吡啶鎓氯化物制备。实施例16—漱口剂(浓缩配方)Ambicin N 1.0％水扬酸苯酯 1.0丙二醇 73.00乙醇(96％) 15.00矫味剂 2.91糖精钠 0.11Tween 20 0.5去离子水 6.48使用浓缩漱口剂是将几滴(大约1ml)稀释于用者漱口盛水用的半玻璃杯(约100ml)中。实施例17—漱口剂(浓缩配方)用实施例16的配方，但用0.075至1.5％如0.75％的十六烷基吡啶鎓氯化物代替水扬酸苯酯。实施例18—漱口剂(浓缩配方)用实施例16的配方，但用0.075至1.5％如0.75％的双氯苯双胍己烷二葡糖酸盐代替水扬酸苯酯。实施例19—漱口片剂Ambicin N 0.9％二氯苯氧氯酚 0.9氟化钠 1.5硬脂酸镁 1.0矫味剂(喷雾干燥) 1.5颜料 0.05柠檬酸(无水) 15碳酸氢钠 11碳酸钠 10木糖醇 适量其它实施例可用山梨糖醇或木糖醇与山梨糖醇的混合物代替木糖醇制备。将各组分混合并压制成500mg的片剂。最好先将柠檬酸，碳酸氢钠和碳酸钠与木糖醇或山梨醇混合。用0.1％的二氯苯氧氯酚可制备其它实施例。使用时，将该片溶于约100ml水中得到起泡的漱口液，然后用者漱口。实施例20—漱口片剂使用实施例19的配方，但用0.9％或0.075％的以氯苯双胍己烷乙酸盐代替二氯苯氧氯酚。实施例21—漱口片剂用实施例19的配方，但只用1.5或0.075％的十六烷基吡啶鎓氯化物代替二氯苯氧氯酚。实施例22—小药囊一起泡口剂Ambicin N 0.225％二氯苯氧氯酚 0.225氟化钠 0.375醇 0.5柠檬酸(无水) 15.0碳酸氢钠 11.0碳酸钠 10.0木糖醇 适量至100可用山梨糖醇或山梨糖醇/木糖醇混合物代替木糖醇。将组份混合并放入2g剂量的小囊中。最好先将碳酸氢钠和碳酸钠分别与木糖醇或山梨糖醇混合。起泡对浓度增加至柠檬酸(22.5％)，碳酸氢钠(16.5％)，和碳酸钠(15％)。用0.0255％的二氯苯氧氯酚制备其它实施例。实施例23—小药囊一起泡漱口剂用实施例22的配方，但只用0.05至0.375％十六烷基吡啶鎓氯化物代替二氯苯氧氯酚。实施例24—小药囊一起泡漱口剂用实施例22的配方，但只用0.025至0.225％双氯苯双胍己烷乙酸盐代替二氯苯氧氯酚。实施例25—Ambicin N的抗细菌范围
用常规标称的抑制浓度(NIC)分析法试验抗一系列口腔重要革兰阴性和革兰阳性细菌化合物来测定Ambicin N(Amb)的抗细菌活性范围，并与十六烷基吡啶鎓氯化物(CPC)，双氯苯双胍己烷(CHX)和二氯苯氧氯酚作比较。结果见表1。在许多例子中，Ambicin N具有优越的活性。但也注意到Ambiein N没有有效抑制念珠菌种的活性。相反，CPC，CHX和TCN都有抗念珠菌的功效。
表1—NIC数据微生物 CPC CHX TCN Amb
(ppm)(ppm)(ppm)(ppm)无乳链球菌 0.78 0.41 4.96 0.22血链球菌 2.12 0.86 0.88 0.23变异链球菌 3.10 3.94 1.11 0.43Strep、milleri 4.58 1.58 1.08 0.14轻型链球菌 2.23 1.50 3.94 0.33绿草链球菌 1.22 4.55 4.23 0.05唾液链球菌 2.36 1.44 4.05 0.18酿脓链球菌 0.78 0.16 4.35 0.009金黄包葡萄球菌 0.66 0.54 0.09 0.13G.Vaginalis 0.3 1.3 0.41 0.22龋齿乳杆菌 0.83 1.88 7.49 0.02龋齿放线菌 1.23 3.37 3.02 0.12衣氏放线菌 8.15 4.11 3.19 0.53内斯兰德放线菌 4.61 2.01 1.98 ＞12.8伴放线菌放线杆菌 1.02 0.53 1.69 0.02具核梭杆菌 0.82 0.64 1.6 0.048中间型乳杆菌 4.68 2.49 3.72 0.91微小消化链球菌 4.96 8.46 6.76 ＞1.28Porph.gingiyalis 0.94 2.36 4.00 ＞1.28Bact.ureolyticus 0.56 0.69 7.65 0.035白色念珠菌 1.39 1.71 1.00 ＞128Candida Kefyr 0.61 0.42 0.46 ＞128Candida tropicalis 0.48 0.98 0.35 ＞128实施例26—Ambicin N的抗细菌范围
用一般的区带扩散分析法测定在含有或不含十六烷基吡啶鎓氯化物(CPC)，双氯苯双胍己烷(CHX)或二氯苯氧氯酚(TCN)(500ppm)之一时，Ambicin N(Amb)(500ppm)液对重要的口腔微生物血链球菌，变异链球菌，伴放线菌放线杆菌，W.recta具核梭杆菌，白色念珠菌，C.Kefyr和C.tropicalis的抗细菌活性。分别用十六烷基吡啶鎓氯化物，二氯苯双胍己烷或二氯苯氧氯酚重复进行分析。结果列于表2和表3中。尽管没有迹象表明Ambicin N和任意十六烷基吡啶鎓氯化物，双氯苯双胍己烷或二氯苯氧氯酚之间存在任何程度的协同作用，但数据也表明在其它一种试剂存在时，两个任何试剂的活性都没有降低，即有相互相溶性。表2：区带扩散分析—抗各种口腔细菌所得的中间区带(mm)
表3：区带扩散分析—抗各种念珠菌种所得的中间区带(mm)
| 血链球菌NCTC10904 | 变异链球菌NCTC11061 | 伴放线菌放线杆菌NCTC9709 | W rectaNCTC11489 | 具核梭杆菌NCTC10562 | |
| Ambicin N | 15.38 | 18.36 | 23.04 | 28.19 | 29.38 |
| TCN | 28.97 | 32.82 | 35.92 | 37.20 | 33.98 |
| CPC | 14.44 | 17.05 | 19.41 | 17.15 | 18.99 |
| CHX | 22.76 | 29.68 | 35.68 | 32.35 | 36.97 |
| Amb/TCN | 26.73 | 31.47 | 31.28 | 33.08 | 26.11 |
| Amb/CPC | 21.92 | 29.42 | 35％25 | 31.52 | 37.33 |
| Amb/CHX | 14.48 | 17.05 | 19.57 | 20.48 | 19.25 |
| C.kefyrNCTC 3106 | C.tropicalisNCTC 3114 | C.albicansNCTC 3089 | |
| Ambicin N(Amb) | 0 | 0 | 0 |
| TCN | 21.99 | 13.66 | 16.99 |
| CPC | 10.43 | 10.39 | 9.79 |
| CHX | 17.03 | 17.36 | 14.93 |
| Amb/TCN | 18.66 | 11.77 | 16.74 |
| Amb/CPC | 16.21 | 17.45 | 14.58 |
| Amb/CHX | 10.66 | 9.98 | 9.74 |
Claims (11)
1.一种口用卫生低阴离子组合物，其中包括一种有效用量的乳酸链球菌肽、一种口腔可接受的选自双氯苯双胍己烷或其盐、十六烷基吡啶鎓氯化物或三氯苯氧氯酚的抗微生物剂；和一种口腔可接受的载体或赋形剂，所述组合物具有低阴离子或无阴离子存在。
2.如权利要求1的组合物，其中所用的乳酸链球菌肽是纯化形式。
3.如权利要求1或2的组合物，其中口腔可接受的载体或赋形剂中所包含的表面活性剂是非离子、阳离子或两性表面活性剂或其混合物。
4.如权利要求1至3中任一权利要求的组合物，其中口腔可接受的载体或赋形剂含有非离子稠化剂或天然或合成胶或胶类物质。
5.如权利要求1至4中任一权利要求的组合物，该组合物是一种洁牙剂，其中磨擦剂是低阴离子二氧化硅磨擦剂。
6.一种低阴离子洁牙组合物，其中含有乳酸链球菌肽；选自十六烷基吡啶鎓氯化物、双氯苯双胍己烷盐或三氯苯氧氯酚的抗微生物剂；非离子表面活性剂；非离子稠化剂；润湿剂；和磨擦剂，该磨擦剂是“低阴离子”硅石或碳酸钙，可任选与正单磷酸二钙组合，且包括碱土金属盐如氯化钙。
7.一种低阴离子洁牙组合物，其中含有乳酸链球菌肽；选自十六烷基吡啶鎓氯化物或三氯苯氧氯酚的抗微生物剂；非离子表面活性剂；任意与稠化硅石混合的羧甲基纤维素钠增稠剂；润湿剂；和“低阴离子”硅石磨擦剂。
8.如以上任一权利要求的组合物，其中还含有口腔可接受的螯合剂。
9.如权利要求8的组合物，其中口腔可接受的螯合剂是EDTA、柠檬酸或其碱金属盐。
10.如权利要求1至3中任一权利要求的组合物的用途，该组合物是漱口剂。
11.如权利要求1至5中任一权利要求的组合物的用途，所述组合物为洁牙剂。
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| GB9224598.4 | 1992-11-24 | ||
| GB929224598A GB9224598D0 (en) | 1992-11-24 | 1992-11-24 | Novel compositions |
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| EP (1) | EP0670711B1 (zh) |
| JP (1) | JPH08504404A (zh) |
| CN (1) | CN1047517C (zh) |
| AT (1) | ATE176756T1 (zh) |
| AU (1) | AU674190B2 (zh) |
| CA (1) | CA2149874C (zh) |
| DE (1) | DE69323558T2 (zh) |
| DK (1) | DK0670711T3 (zh) |
| ES (1) | ES2130389T3 (zh) |
| GB (1) | GB9224598D0 (zh) |
| GR (1) | GR3029677T3 (zh) |
| MX (1) | MX9307358A (zh) |
| WO (1) | WO1994012150A1 (zh) |
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| US5496541C1 (en) * | 1993-01-19 | 2001-06-26 | Squigle Inc | Tasteful toothpaste and other dental products |
| CN1066960C (zh) * | 1994-07-19 | 2001-06-13 | 李文兴 | 抗龋齿组合物及其制备方法 |
| IT1274655B (it) * | 1995-02-28 | 1997-07-18 | Smithkline Beecham Farma | Composizioni farmaceutiche contenenti un agente antiinfiammatorio e un agente antimicrobico |
| GB9517113D0 (en) * | 1995-08-21 | 1995-10-25 | Smithkline Beecham Plc | Novel compositions |
| AU728379B2 (en) * | 1995-11-03 | 2001-01-11 | Unilever Plc | Natural composition for combatting fungi |
| JP3493866B2 (ja) * | 1995-12-27 | 2004-02-03 | ライオン株式会社 | 発泡性口腔用組成物 |
| FI974385A0 (fi) | 1997-12-01 | 1997-12-01 | Xyrofin Oy | Anvaendning av xylitol foer bekaempning av jaestinfektion och xylitolpreparat foer denna anvaendning |
| US5958381A (en) * | 1998-03-12 | 1999-09-28 | Colgate Palmolive Company | Bis-biguanide antiplaque dentifrice exhibiting reduced staining |
| EP1159951A1 (en) | 2000-06-02 | 2001-12-05 | Societe Des Produits Nestle S.A. | Use of exogenous lactic bacteria strain against Actinomyces naeslundii-related diseases |
| ES2363201T3 (es) | 1998-08-12 | 2011-07-26 | Societe des Produits Nestlé S.A. | Incorporación de bactérias láctidas exógenas a la microflora oral. |
| KR100555038B1 (ko) * | 1998-12-10 | 2006-06-20 | 주식회사 엘지생활건강 | 나이신과 유지피 추출물을 함유한 구강위생증진용 조성물 |
| KR100665891B1 (ko) * | 2000-05-23 | 2007-01-10 | 주식회사 엘지생활건강 | 하이드록시타이로졸을 함유한 구강위생 증진용 조성물 |
| JP2002128697A (ja) * | 2000-10-20 | 2002-05-09 | Nonomura Tomosuke | 口腔治療予防剤 |
| US6447758B1 (en) * | 2001-05-02 | 2002-09-10 | Colgate Palmolive Company | Cationic antibacterial dentifrice exhibiting superior foaming properties |
| US6835536B2 (en) | 2001-08-21 | 2004-12-28 | Micrologix Biotech Inc. | Antimicrobial cationic peptides and formulations thereof |
| ES2427841T3 (es) * | 2001-11-15 | 2013-11-04 | Laboratorios Miret, S.A. | Uso de un tensioactivo catiónico como mejorador de la actividad antimicrobiana en desodorantes y en el cuidado bucal |
| ES2214135B1 (es) * | 2003-02-21 | 2005-05-01 | Laboratorios Kin S.A. | Composicion para el tratamiento de la cavidad bucal y utilizaciones correspondientes. |
| US8778889B2 (en) | 2003-03-10 | 2014-07-15 | The United States Of America As Represented By The Secretary Of The Army | Antimicrobial decapeptide oral hygiene treatment |
| JP4171406B2 (ja) * | 2003-12-02 | 2008-10-22 | 花王株式会社 | 歯周病予防又は治療用組成物 |
| US7846422B2 (en) | 2003-08-04 | 2010-12-07 | Kao Corporation | Method for prevention or treatment of periodontal diseases and composition for an oral cavity |
| US9241885B2 (en) * | 2004-01-29 | 2016-01-26 | The Procter & Gamble Company | Oral care compositions comprising increased bioavailable levels of quaternary ammonium antimicrobials |
| NZ530915A (en) * | 2004-02-02 | 2004-08-27 | Bernard Charles Sherman | Antimicrobial oral rinse solid composition to be dispersed in water prior to use in the oral cavity |
| JP5963383B2 (ja) * | 2005-06-06 | 2016-08-03 | 株式会社明治 | 口腔ケア用組成物 |
| GB0813211D0 (en) * | 2008-07-18 | 2008-08-27 | E Therapeutics Plc | Antibacterial combination therapy for the treatment of gram positive bacterial infections |
| GB0817121D0 (en) * | 2008-09-18 | 2008-10-29 | Univ St Andrews | Anti-fungal therapy |
| CN104918494A (zh) * | 2012-11-14 | 2015-09-16 | 生态友好研究所株式会社 | 抗菌用组合物 |
| RS60508B1 (sr) * | 2015-01-13 | 2020-08-31 | Acraf | Farmaceutska kompozicija za lečenje mikoza |
| US11304888B2 (en) | 2019-04-29 | 2022-04-19 | Sunstar Americas, Inc. | Oral care composition |
| CA3176461A1 (en) * | 2020-05-08 | 2021-11-11 | Fertin Pharma A/S | Mouthwash for oral care benefits |
| US11819561B2 (en) * | 2020-06-26 | 2023-11-21 | Colgate-Palmolive Company | Oral care compositions |
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| EP0140498A1 (en) * | 1983-08-11 | 1985-05-08 | Lion Corporation | Caries-preventive composition |
| US4714612A (en) * | 1984-06-28 | 1987-12-22 | Lion Corporation | Composition for oral application |
| US4980163A (en) * | 1989-03-01 | 1990-12-25 | Public Health Research Institute Of The City Of New York | Novel bacteriocin compositions for use as enhanced broad range bactericides and methods of preventing and treating microbial infection |
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| CA2149874A1 (en) | 1994-06-09 |
| AU5530994A (en) | 1994-06-22 |
| AU674190B2 (en) | 1996-12-12 |
| DE69323558T2 (de) | 1999-06-17 |
| WO1994012150A1 (en) | 1994-06-09 |
| DK0670711T3 (da) | 1999-05-10 |
| ZA938702B (en) | 1994-08-11 |
| CN1101254A (zh) | 1995-04-12 |
| JPH08504404A (ja) | 1996-05-14 |
| EP0670711B1 (en) | 1999-02-17 |
| DE69323558D1 (de) | 1999-03-25 |
| EP0670711A1 (en) | 1995-09-13 |
| ES2130389T3 (es) | 1999-07-01 |
| ATE176756T1 (de) | 1999-03-15 |
| GB9224598D0 (en) | 1993-01-13 |
| MX9307358A (es) | 1994-05-31 |
| CA2149874C (en) | 2002-04-23 |
| GR3029677T3 (en) | 1999-06-30 |
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