Oral care compositions

Details Oral care compositions Oral care compositions

1999-09-23

2001-09-11

Rose, Shep K. (Department: 1614)

Drug, bio-affecting and body treating compositions

Dentifrices

C514S184000, C514S189000, C424S630000, C424S642000, C424S646000, C424S647000, C424S648000, C424S650000

Reexamination Certificate

active

06287541

ABSTRACT:

BACKGROUND OF THE INVENTION
1. The present invention relates to oral care compositions comprising particular antiplaque agents. More particularly, it relates to oral care compositions comprising certain copper, zinc, iron or tin metal complexes comprising biologically active ligands as antiplaque agents.
2. The Related Art
It is already known, that copper and zinc metals complexes comprising certain biologically active ligands have an antimicrobial activity. Thus, for example, in EP-A-0728478 (Otsuka Pharmaceutical Co., Ltd.), copper-hinokitiol and zinc-hinokitiol complexes are described, which are stated to have antimicrobial activity. According to this publication, these copper- and zinc-hinokitiol complexes can be usefully included in oral care compositions.
Hinokitiol is a 4-isopropyl tropolone, a cyclic &agr;-hydroxyketone having the structure
SUMMARY OF THE INVENTION
We have now found that a different class of cyclic &agr;-hydroxyketones are biologically active ligands, capable of forming complexes with copper, zinc, iron and tin, said complexes having an antiplaque activity which is superior to the aforementioned copper- and zinc-hinokitiol complexes.
The class of cyclic &agr;-hydroxyketones according to the present invention is represented by the following general structural formula:
in which X represents O or NR
3
, R
1
and R
3
represent H or a C
1
-C
16
, preferably a C
1
-C
4
branched or straight-chain alkylgroup, and R
2
represents H or a hydroxymethylgroup. The link between the carbon atoms in the ring structure at positions 2 and 3 can be saturated or unsaturated, and is preferably unsaturated.
This class of cyclix &agr;-hydroxyketones embraces, therefore, derivatives of hydroxypyran-4-ones and hydroxypyridin-4-ones. Typical examples of these cyclic &agr;-hydroxyketones are maltol (=3-hydroxy-2-methyl-4H-pyran-4-one), X being
0
, R
1
being methyl and R
2
being H; ethylmaltol (3-hydroxy-2-ethyl-4H-pyran-4-one), X being O, R
1
being ethyl and R
2
being H; kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one), X being O, R
1
being H and R
2
being hydroxymethyl; 2-methyl-3-hydroxypyridin-4-one, X=NR
1
, R
3
=H, R
1
=methyl and R
2
=H; 1,2-dimethyl-3-hydroxypyridin-4-one, X=NR
3
, R
3
=methyl, R
1
=methyl and R
2
=H; and 1-ethyl-2-methyl-3-hydroxypyridin-4-one, X=NR
3
,R
3
=ethyl, R
1
=methyl and R
2
=H.
The metals which are complexed by the above class of cyclic &agr;-hydroxyketones are divalent copper, zinc, iron and tin and trivalent iron.
DETAILED DESCRIPTION OF THE INVENTION
The cyclic &agr;-hydroxyketones of the present invention, and the metal complexes thereof, are known in the art and can be synthesised by established methodologies, as e.g. described in Acta Cryst. B32 (1976) page 3121 by Berg, et al., in Can. J. Chem. 68, (1990) page 1598 by Annan, et al., J. Chem. Soc., Dalton Trans. (1992) page 2375 by Denekamp, et al., in J. Med. Chem. 37 (1994 page 461 by El-Jammal, et al., and in J. Med. Chem. 39 (1996) page 3659 by Ellis, et al.. Suitable complexes can be formed from a suitable divalent copper, zinc, iron or stannous salt or a trivalent iron salt with the cyclic &agr;-hydroxyketones in molar ratios of between 10:1 to 1:10, preferably 4:1 to 1:4, particularly preferably 2:1 to 1:2 (the molar ratio being calculated on the basis of the metal ion).
The preferred metal complexes according to the present invention are the Cu
2−
and Sn
2−
complexes, particularly the Cu
2+
- and Sn
2:
malton and -ethylmalton complexes.
The metal complexes of the present invention are included in the oral care compositions in an amount, ranging from 0.001 to 5% by weight of the composition, preferably 0.1 to 3% by weight, and optimum results are obtained with amounts, ranging from 0.2 to 2 by weight of the composition. Mixtures of the various metal complexes may also be used. The complexes may be prepared prior to their incorporation in the oral care composition, or they may be prepared in situ during the manufacture of the oral care composition. It may sometimes be advantageous to use an amount of the cyclic &agr;-hydroxyketone, in excess of the stochiometric equivalent, required for the formation of the complex, to prevent possible decomposition of the complexes in the oral care composition during storage, and to possibly further increase the antiplaque activity of the complexes. It has also been found that it is sometimes advantageous to use an excess of the metal salt, e.g. the copper or stannous salt, to further increase the antiplaque activity.
The oral care compositions of the present invention may furthermore comprise optional, conventional ingredients such as pharmaceutically acceptable carriers like starch, sucrose, water or water/alcohol systems etc.. Small amounts of surfacants may also be included, such as anionic, nonionic, cationic and zwitterionic or amphoteric surfacants. They may comprise particulate abrasive materials such as silicas, aluminas, calcium carbonates, dicalciumphosphates, calcium pyrophosphates, hydroxyapatites, trimetaphosphates, insoluble hexametaphosphates and so on, including agglomerated particulate abrasive materials, usually in amounts between 3 and 60% by weight. In the case of the calcium carbonates being used as the abrasive materials, the metal complexes of the present invention are more compatible with such materials than other metal salts, e.g. copper salts, which are according to EP-B-38867 (Blendax) rather incompatible with calcium carbonates.
Furthermore, they may comprise humectants such as glycerol, sorbitol, propyleneglycol, xylitol, lactitol and so on.
Binders and thickeners such as sodium carboxymethyl-cellulose, xanthan gum, gum arabic etc. may also be included, as well as synthetic polymers such as polyacrylates and carboxyvinyl polymers such as Carbopol®.
Flavours such as peppermint and spearmint oils may also be included, as well as preservatives, opacifying agents, colouring agents, pH-adjusting agents, sweetening agents and so on.
Additional anti-bacterial agents may also be included such as Triclosan, chlorohexidine, copper-, zinc- and stannous salts such as zinc citrate, sodium zinc citrate and stannous pyrophosphate, sanguinarine extract, metronidazole. Further examples of anti-bacterial agents are quaternary ammonium compounds such as cetylpyridinium chloride; bis-guanides such as chlorhexidine digluconate, hexetidine, octenidine, alexidine; halogenated bisphenolic compounds such as 2,2′ methylenebis-(4-chloro-6-bromophenol).
Polymeric compounds which can enhance the delivery of active ingredients such as anti-bacterial agents can also be included. Examples of such polymers are copolymers of polyvinylmethylether with maleic anhydride and other similar delivery enhancing polymers, e.g. those described in DE-A-3,942,643 (Colgate)
While the complexes of the present invention are particularly useful as anti-plaque agents, they are also useful as antimicrobial- and anti-gingivitis agents in oral care products.
Furthermore anti-inflammatory agents such as ibuprofen, flurbiprofen, aspirin, indomethacin etc. may also be included.
Anti-caries agents such as sodium- and stannous fluoride, aminefluorides, sodium monofluorophosphate, casein, plaque buffers such as urea, calcium lactate, calcium glycerophosphate, strontium polyacrylates may also be included. Other optional ingredients include vitamins such as Vitamin C, and plant extracts. Desensitizing agents such as glycerolmonooleate potassium citrate, potassium chloride, potassium tartrate, potassium bicarbonate, potassium oxalate, potassium nitrate as well as strontium salts may also be included.
Buffers and salts to buffer the pH and ionic strength of the compositions may also be included. Liposomes and other encapsulates may also be used to improve delivery or stability of active ingredients.
Furthermore, the oral compositions may comprise anti-calculus agents such as alkalimetal pyrophosphates, hypophosphite-containing polymers, organic pho

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