Zinc citrate/Triclosan: a new antiplaque system for the control of plaque and the prevention of gingivitis: short-term clinical and mode of action studies
D. Cummins Unilever Dental Research, Port Sunlight Laboratory Quarry Road East, Bebington, Wirral L63 3JW, UK
Cummins D: Zinc citrateI Triclosan: a new anti-plaque system for the control of plaque and the prevention of gingivitis: short-term clinical and mode of action studies. J Clin Periodontol 1991; 18: 455-461. Abstract. A dentifrice based upon the additive anti-plaque effects of zinc citrate and Triclosan has been developed and optimised for clinical activity. In 16-h and 4-day plaque growth inhibition studies, zinc citrate/Triclosan inhibited plaque accumulation significantly more than either agent alone. The effect on the development of gingivitis has been demonstrated in a 21-day experimental gingivitis study. ZCT/Triclosan reduced the development of gingival bleeding sites by significantly more than ZCT alone, suggesting that the system has the potential to give a gingival health benefit in a 6-month unsupervised brushing study. Zinc and Triclosan employ multiple modes of antimicrobial action and these result in reduced growth, inhibition of glucose uptake and metabolism and modified virulence of periodontal pathogens. Importantly, the effects of zinc and Triclosan are additive and complementary. Oral substantivity is a pre-requisite of any agent for anti-plaque activity in vivo. Pharmacokinetic data demonstrate that ~ 3 0 % of the zinc and Triclosan dosed is retained immediately after brushing. Saliva decay curves indicate that Triclosan is cleared more quickly from the mouth than zinc, consistent with the physicochemical properties of these agents. Triclosan is present in plaque for at least 8 h and in the oral mucosa for at least 3 h after brushing.
The rationale for the use of Triclosan system. It covers the folantimicrobial/anti-plaque agents to lowing. control supragingival plaque formation • Short-term clinical studies which demonstrate the potential of the sysand to prevent the onset of early peritem to deliver long term clinical odontal disease is clear (Kornman 1986, benefit. Ciancio 1989, Van der Ouderaa 1990). In principle, toothpastes provide an ex- • In vitro microbiological data which illustrate the complementary and adcellent vehicle for the delivery of such ditive anti-microbial properties of agents. However, very few have been zinc citrate and Triclosan. successfully formulated to give clinically active products (Van der Ouderaa & • Pharmacokinetic studies of the retenCummins 1989, Van der Ouderaa 1991). tion of zinc and Triclosan which demA dentifrice based upon the additive onstrate why these agents are able to anti-plaque effects of low levels of zinc exert their anti-microbial effects in citrate and Triclosan has recently been vivo. :'emonstrated to deliver significant laque and gingival health benefits durlg six months unsupervised daily use Short-Term Clinical Studies Svatun et al. 1990, Stephens et al. ?90), This paper reviews data which The clinical benefits of combining zinc ,ipport the benefits of this zinc citrate/ citrate and Triclosan have been demon-
Key words: zinc citrate; Triclosan; plaque gingivitis; clinical, microbiological; pharmacokinetics. Accepted for publication 19 December 1990
strated using a hierarchy of well established protocols, namely: • 16-h plaque growth inhibition test (Harrap 1974); • 4-day plaque growth inhibition test (Addy et al. 1983); • 21-day experimental gingivitis model (Saxton & Van der Ouderaa 1989). In both 16-h (Saxton et al. 1987, Saxton et al. 1988) and 4-day (Saxton 1986) non-brushing studies, zinc citrate/ Triclosan inhibited plaque accumulation significantly more than either zinc citrate or Triclosan alone. The data from these studies are collated in Table 1. Numerous studies have subsequently confirmed these findings; 16-h plaque growth inhibition data show an average reduction of > 3 5 % for the optimised 0.5% zinc citrate/0.2% Triclosan formulation compared to a control tooth-
456
Cummins
Table 1. The effects of dentifrices containing zinc citrate and Triclosan on the accumulation of plaque Mean regrowth , ; of gingival . margin Mean % Test Plaque (%) plaque area Ref Product Study type 16-h, single application
placebo ZCT ZCT/TCN
16-h. single application
placebo TCN ZCT/TCN
16-h, single application
placebo ZCT ZCT/TCN
4-day, twice daily application of 23% aqueous slurry
placebo ZCT TCN ZCT/TCN
paste and MIC levels) together with the effects from retention in the oral cavity
60
o LL
o
40
GQ
20
Table 3. The effect of dentifrices containing 0.5% and 1.0% zinc citrate on the accumulation of plaque and the development gingivitis in a 21 -day experimental gingivitis study (Saxton & Cummins 1989) 1
2
ADSORPTION OF ZINC
1
6
8
10
Zn/mg dry wt. cells)
Fig. 1. The correlation between inhibition of acid production and adsorption of zinc to Streptococcus mutans NCTC 10449 in assay systems containing zinc sulphate (•), zinc citrate (0) and zinc EDTA (D) (Watson et al. 1991)
Test product placebo 0.5% ZCT 1.0% ZCT
Mean % Mean % gingiva' plaque area bleeding at day 21 day 0 day 21 46.5 33.9 36.4
12.1 12.0 15.5
48.8 36.9 40.7
Plaque control: mechanistic aspects (at sub-MIC levels) between brushings. on the cell surface (Glantz and Attstrom The latter are presumably the dominant 1986) and, hence, increasing coaggregaeffects for agents, such as chlorhexidine, tion. A major role of zinc has been prometal ions, Triclosan, etc, with good posed to be one of the inhibition of oral substantivity. Zinc and Triclosan almost certainly glucose metabolism. Using a novel, act multifunctionally, with complement- chemically defined pH-stat assay system ary modes of action, to reduce bacterial (Cummins & Watson 1989) zinc adgrowth, to inhibit metabolism and to sorption to Streptococcus mutans NCTC 10449 has been demonstrated modify bacterial virulence. With respect to effects on bacterial and this adsorption has been shown to growth, recent studies using a well result in the inhibition of the metabcharacterised mixed culture system olism of glucose to lactic acid (Fig. 1). (McKee et al. 1985) have demonstrated More importantly, the chemical composynergy for the combination of zinc sition of the zinc species has been shown citrate and Triclosan, with marked to be the key factor in determining the specificity towards organisms associ- biological activity of zinc as a metabolic ated with disease, such as Streptococcus inhibitor (Watson & Cummins 1988, mutans, Porphyromonas gingivalis and Cummins & Watson 1989). In summary, Bacteriodes intermedius (Marsh 1991). the anti-microbial effects of zinc are reZinc may reduce bacterial colonis- duced by complexation. In systems conation and subsequent plaque matu- taining citrate or EDTA, anti-microbial ration by modifying the cell surface activity is directly proportional to the properties of individual plaque bacteria concentration of free zinc ion, indiat either "adhesion" or "receptor" sites. eating that Zn^q+ is the bioactive form Some evidence suggests that zinc may of zinc in these test systems. Bioactivity act directly by altering cell proteins (Jo- was not always reduced to zero in exnes et al. 1988) or indirectly by inhibit- periments where the concentration of il^ was minimised by the addition of ing protease induced adhesion (Li & Ellen 1990). Alternatively, zinc may sim- alternative ligands such as the amino ply bind to cell surface proteins (Hanke acids histidine, glycine or eysteine. This 1940), reducing the next negative charge indicates that some positively charged
100
g o D n
80
o Q. Q
60
O
D. Cummins Unilever Dental Research, Port Sunlight Laboratory Quarry Road East, Bebington, Wirral L63 3JW, UK
Cummins D: Zinc citrateI Triclosan: a new anti-plaque system for the control of plaque and the prevention of gingivitis: short-term clinical and mode of action studies. J Clin Periodontol 1991; 18: 455-461. Abstract. A dentifrice based upon the additive anti-plaque effects of zinc citrate and Triclosan has been developed and optimised for clinical activity. In 16-h and 4-day plaque growth inhibition studies, zinc citrate/Triclosan inhibited plaque accumulation significantly more than either agent alone. The effect on the development of gingivitis has been demonstrated in a 21-day experimental gingivitis study. ZCT/Triclosan reduced the development of gingival bleeding sites by significantly more than ZCT alone, suggesting that the system has the potential to give a gingival health benefit in a 6-month unsupervised brushing study. Zinc and Triclosan employ multiple modes of antimicrobial action and these result in reduced growth, inhibition of glucose uptake and metabolism and modified virulence of periodontal pathogens. Importantly, the effects of zinc and Triclosan are additive and complementary. Oral substantivity is a pre-requisite of any agent for anti-plaque activity in vivo. Pharmacokinetic data demonstrate that ~ 3 0 % of the zinc and Triclosan dosed is retained immediately after brushing. Saliva decay curves indicate that Triclosan is cleared more quickly from the mouth than zinc, consistent with the physicochemical properties of these agents. Triclosan is present in plaque for at least 8 h and in the oral mucosa for at least 3 h after brushing.
The rationale for the use of Triclosan system. It covers the folantimicrobial/anti-plaque agents to lowing. control supragingival plaque formation • Short-term clinical studies which demonstrate the potential of the sysand to prevent the onset of early peritem to deliver long term clinical odontal disease is clear (Kornman 1986, benefit. Ciancio 1989, Van der Ouderaa 1990). In principle, toothpastes provide an ex- • In vitro microbiological data which illustrate the complementary and adcellent vehicle for the delivery of such ditive anti-microbial properties of agents. However, very few have been zinc citrate and Triclosan. successfully formulated to give clinically active products (Van der Ouderaa & • Pharmacokinetic studies of the retenCummins 1989, Van der Ouderaa 1991). tion of zinc and Triclosan which demA dentifrice based upon the additive onstrate why these agents are able to anti-plaque effects of low levels of zinc exert their anti-microbial effects in citrate and Triclosan has recently been vivo. :'emonstrated to deliver significant laque and gingival health benefits durlg six months unsupervised daily use Short-Term Clinical Studies Svatun et al. 1990, Stephens et al. ?90), This paper reviews data which The clinical benefits of combining zinc ,ipport the benefits of this zinc citrate/ citrate and Triclosan have been demon-
Key words: zinc citrate; Triclosan; plaque gingivitis; clinical, microbiological; pharmacokinetics. Accepted for publication 19 December 1990
strated using a hierarchy of well established protocols, namely: • 16-h plaque growth inhibition test (Harrap 1974); • 4-day plaque growth inhibition test (Addy et al. 1983); • 21-day experimental gingivitis model (Saxton & Van der Ouderaa 1989). In both 16-h (Saxton et al. 1987, Saxton et al. 1988) and 4-day (Saxton 1986) non-brushing studies, zinc citrate/ Triclosan inhibited plaque accumulation significantly more than either zinc citrate or Triclosan alone. The data from these studies are collated in Table 1. Numerous studies have subsequently confirmed these findings; 16-h plaque growth inhibition data show an average reduction of > 3 5 % for the optimised 0.5% zinc citrate/0.2% Triclosan formulation compared to a control tooth-
456
Cummins
Table 1. The effects of dentifrices containing zinc citrate and Triclosan on the accumulation of plaque Mean regrowth , ; of gingival . margin Mean % Test Plaque (%) plaque area Ref Product Study type 16-h, single application
placebo ZCT ZCT/TCN
16-h. single application
placebo TCN ZCT/TCN
16-h, single application
placebo ZCT ZCT/TCN
4-day, twice daily application of 23% aqueous slurry
placebo ZCT TCN ZCT/TCN
paste and MIC levels) together with the effects from retention in the oral cavity
60
o LL
o
40
GQ
20
Table 3. The effect of dentifrices containing 0.5% and 1.0% zinc citrate on the accumulation of plaque and the development gingivitis in a 21 -day experimental gingivitis study (Saxton & Cummins 1989) 1
2
ADSORPTION OF ZINC
1
6
8
10
Zn/mg dry wt. cells)
Fig. 1. The correlation between inhibition of acid production and adsorption of zinc to Streptococcus mutans NCTC 10449 in assay systems containing zinc sulphate (•), zinc citrate (0) and zinc EDTA (D) (Watson et al. 1991)
Test product placebo 0.5% ZCT 1.0% ZCT
Mean % Mean % gingiva' plaque area bleeding at day 21 day 0 day 21 46.5 33.9 36.4
12.1 12.0 15.5
48.8 36.9 40.7
Plaque control: mechanistic aspects (at sub-MIC levels) between brushings. on the cell surface (Glantz and Attstrom The latter are presumably the dominant 1986) and, hence, increasing coaggregaeffects for agents, such as chlorhexidine, tion. A major role of zinc has been prometal ions, Triclosan, etc, with good posed to be one of the inhibition of oral substantivity. Zinc and Triclosan almost certainly glucose metabolism. Using a novel, act multifunctionally, with complement- chemically defined pH-stat assay system ary modes of action, to reduce bacterial (Cummins & Watson 1989) zinc adgrowth, to inhibit metabolism and to sorption to Streptococcus mutans NCTC 10449 has been demonstrated modify bacterial virulence. With respect to effects on bacterial and this adsorption has been shown to growth, recent studies using a well result in the inhibition of the metabcharacterised mixed culture system olism of glucose to lactic acid (Fig. 1). (McKee et al. 1985) have demonstrated More importantly, the chemical composynergy for the combination of zinc sition of the zinc species has been shown citrate and Triclosan, with marked to be the key factor in determining the specificity towards organisms associ- biological activity of zinc as a metabolic ated with disease, such as Streptococcus inhibitor (Watson & Cummins 1988, mutans, Porphyromonas gingivalis and Cummins & Watson 1989). In summary, Bacteriodes intermedius (Marsh 1991). the anti-microbial effects of zinc are reZinc may reduce bacterial colonis- duced by complexation. In systems conation and subsequent plaque matu- taining citrate or EDTA, anti-microbial ration by modifying the cell surface activity is directly proportional to the properties of individual plaque bacteria concentration of free zinc ion, indiat either "adhesion" or "receptor" sites. eating that Zn^q+ is the bioactive form Some evidence suggests that zinc may of zinc in these test systems. Bioactivity act directly by altering cell proteins (Jo- was not always reduced to zero in exnes et al. 1988) or indirectly by inhibit- periments where the concentration of il^ was minimised by the addition of ing protease induced adhesion (Li & Ellen 1990). Alternatively, zinc may sim- alternative ligands such as the amino ply bind to cell surface proteins (Hanke acids histidine, glycine or eysteine. This 1940), reducing the next negative charge indicates that some positively charged
100
g o D n
80
o Q. Q
60
O
