Drug – bio-affecting and body treating compositions – Dentifrices
Reexamination Certificate
1999-04-23
2001-06-12
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Dentifrices
C424S058000
Reexamination Certificate
active
06245321
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to dental products comprising cyclodextrins.
Dental plaque is present to some degree, in the form of a film, on virtually all dental surfaces. It is a by-product of microbial growth, and comprises a dense microbial layer consisting of a mass of micro-organisms embedded in a polysaccharide matrix. The micro-organisms present in plaque are mainly coccoidal organisms, particularly in early plaque. As plaque ages and matures, gram negative anaerobes and filamentous organisms appear and become more common after a few days. Plaque itself adheres to dental surfaces and may not be removed completely even with a rigorous brushing regimen and can build up, for example, in recessed areas of tooth surfaces, such as approximal regions and fissures. Moreover, plaque rapidly reforms on the tooth surface after it is removed.
Plaque may form on any part of the tooth surfaces, and can be found particularly at the gingival margin, in pits and fissures in the enamel, and on the surface of dental calculus. The danger associated with the formation of plaque on the teeth lies in the tendency of plaque to build up and eventually contribute to gingivitis, periodontitis and other types of periodontal disease, as well as dental caries and dental calculus.
More specifically, dental plaque is a precursor to the formation of the hard crystalline build up on teeth referred to as dental calculus. Both the bacterial and the nonbacterial components of plaque mineralize to form calculus, which comprises mineralized bacteria as well as organic constituents, such as epithelial cells, live bacteria, salivary proteins, leukocytes, and crystalline substances containing both calcium and phosphorous, e.g., hydroxyapatite, Ca
10
(PO
4
)
6
(OH)
2
, octacalcium phosphate, Ca
8
(HPO
4
)
2
(PO
4
)
4
.5H
2
O, brushite, CaHPO
4−
.2H
2
O, and whitlockite, which is considered to have the formula &bgr;-Ca
3
(PO
4
)
2
. Dental plaque and, hence, calculus are particularly prone to form at the gingival margin. i.e.. the junction of the tooth and gingiva. The buildup of plaque at, and below. The gingival margin is believed to be the prime cause of gingivitis and periodontal disorders.
Mouthwashes have been formulated to contain antimicrobial ingredients whose function is to reduce the buildup of plaque, either by the direct bactericidal action (i.e. killing) on plaque and salivary micro-organisms and by bacteriostatic action (i.e. growth inhibition) on plaque and salivary micro-organisms. Scheie, A. AA. (1989) Modes of Action of Currently Known Chemical Anti-Plaque Agents Other than Chlorhexidine. J. Dent. Res. 68 Special Issue: 1609-1616. Oral compositions including mouthwashes and dentifrices containing phenolic compounds are referred to in U.S. Pat. Nos. 4,945,087; WO 94/16.16,674; WO 94/07477; and WO 94/18939. Oral composition including triclosan are referred to in the following: U.S. Pat. Nos. 4,892,220; 5,032,386; 5,037,637; 5,034,154; 5,080,887; 5,236,699; 5,043,154; 5,032,385; and 5,156,835 as well as EPO 85303216.7.
However phenolics useful in oral compositions have low aqueous solubilities which limit their use in oral compositions and they require high levels of either 1) alcohol; 2) surfactants; or 3) co-solvents or combinations of the above for sufficient solubility in the carrier. PCT Appln No. WO 94/16674.
For example, thymol has been used as a anthelmintic and antiseptic, in mouthwashes containing a combination of menthol, methyl salicylate, eucalyptol and thymol. However, these compositions are characterized by their relatively high alcohol levels which causes them to have negative aesthetics, including excessive “bite” and “burn.”
Triclosan (2,4,4′-trichloro-2′-hydroxydiphenyl ether) is a phenolic, nonionic antimicrobial agent used in various soap and toiletry products. In the oral care area, triclosan has been used as a plaque-inhibitory agent in various toothpastes and mouthrinses. Triclosan is a broad-spectrum antimicrobial that has shown activity in in vitro assays. Regos, J. and Hitz, H. R. (1974) Investigation of Mode of Action of Triclosan, A Broad Spectrum Antimicrobial Agent. Zbl Bakt Hyg I Abt Orig A 226:390-401; Vischer, W. A. and Regos, J. (1974) Antimicrobial Spectrum of Triclosan, A Broad-Spectrum Antimicrobial Agent for Topical Application. Zbl Bakt Hyg I Agt Orig A 226:376-389, including chemostat studies; Bradshaw, D. J., Marsh, P. D., Watson, G. K. and Cummins, D. (1993) The Effects of Triclosan and Zinc Citrate, Alone and in Combination, on a Community of Oral Bacteria Grown in vitro. J. Dent Res. 72:25-30; Herles, S., Olsen, S., Afflito, J. and Gaffar, A. (1994) Chemostat Flow Cell System: An in vitro Model for the Evaluation of Antiplaque Agents. J. Dent Res. 73:1748-1755, as well as animal tests; Nabi, N., Mukerjee, C., Schmid, R., Gaffar, A. (1989) In Vitro and In Vivo Studies on Triclosan/PVM/MA copolymer/NaF Combination as an Antiplaque Agent. Am. J. Dent. Spec Issue No. 2: 197-206; and human clinical studies; Garcia-Godoy, F., Garcia-Godoy, F., DeVizio, W., Volpe, A. R., Ferlauto. R. J. and Miller, J. M. (1990) Effect of a Triclosan/Copolymer/Fluoride Dentifrice on Plaque Formation and Gingivitis: A 7-month Clinical Study. Am. J. Dent. 3:S15-S26; Rustogi, K. N., Petrone, D. M., Singh, S. M., Volpe, A. R. and Tavss, E. (1990) Clinical Study of a Pre-brush and Triclosan/Copolymer Mouthrinse: Effect on Plaque Formation. Am. J. Dent. 3:S67-S69; and Saxton. C. A., Lane, R. M. and van der Ouderaa, F. (1987) The Effects of a Dentifrice Containing a Zinc Saft and a Non-cationic Antimicrobial Agent on Plaque and Gingivitis. J. Clin. Periodontol. 57:555-561. Although triclosan when delivered orally, is taken up by plaque and is moderately substantive, its bioactivity is limited by its poor aqueous solubility. Thus, triclosan has to be solubilized either by alcohol or surfactants such as sodium lauryl sulfate when formulated into a conventional dentifrice or mouthrinse product. Kjaerheim, V., Waaler, S. M., Rolla, G. (1994) Significance of Choice of Solvents for the Clinical Effect of Triclosan-containing Mouthrinses. Scand. J. Dent. Res. 102.202-205.
Cyclodextrins are known to form inclusion complexes with various compounds. The cyclodextrin molecule consists of glucopyranose units arranged in a torus-like or donut-like configuration having all the secondary hydroxyl groups located on one side of the torus and all primary hydroxyl groups located on the other side. Alpha, beta, and gamma cyclodextrin contain 6, 7 & 8 cyclic glucopyranose units, respectively, in the torus shell. The “lining” of the internal cavity is formed by hydrogen and glucosidic oxygen-bridge atoms and therefore the surface is slightly apolar.
SUMMARY OF THE INVENTION
The present invention relates to an oral rinse composition, comprising:
a) from about 0.01% to about 2.5% by weight of a phenolic, said phenolic selected from the group consisting of menthol, eucalyptol, methyl salicylate, thymol, triclosan, and mixtures thereof;
b) From about 0. 1% by weight to about 25% by weight of a cyclodextrin, said cyclodextrin selected from the group consisting of hydroxypropyl &bgr;-cyclodextrin, hydroxyethyl &bgr;-cyclodextrin, hydroxypropyl &ggr;-cyclodextrin, hydroxyethyl &ggr;-cyclodextrin, &agr;-cyclodextrin, methyl &bgr;-cyclodextrin, and mixtures thereof;
c) Up to about 25% by weight ethanol; and
d) an orally acceptable carrier.
The present invention also relates to a dentifrice in the form of a toothpaste or tooth gel, comprising:
a) from about 0.01% to about 10% by weight of a phenolic, said phenolic selected from the group consisting of menthol, eucalyptol, methyl salicylate, thymol, triclosan, and mixtures thereof;
b) From about 0.1% by weight to about 60% by weight of a cyclodextrin, said cyclodextrin selected from the group consisting of hydroxypropyl &bgr;-cyclodextrin, hydroxyethyl &bgr;-cyclodextrin, hydroxypropyl &ggr;-cyclodextrin, hydroxyethyl &ggr;-cyclodextrin, &agr;-cyclodextrin, methyl &bgr;-cyclodextrin, and mixtures thereof;
c) up to about
Nelson Dennis G. A.
Sheehan Craig J.
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Rose Shep K.
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