The Evolution of Colgate Total®: A New Era Stabilized by Nitrate and Phosphates

Lisa M. Manus, PhD; Carl P. Myers, PhD; Robert D’Ambrogio, BS; Gokul V. Govindaraju, PhD; Guofeng Xu, PhD; Yun-Po Zhang, PhD, DDS (Hon); and James G. Masters, PhD

The tipping point between oral health and disease is influenced by a variety of inherent and environmental risk factors. The health of the oral cavity can be impacted by genetics, diet, accessibility to routine dental care, perceptions of and past experiences with dental professionals, socioeconomic status, and daily oral hygiene practices.^1-4 Despite scientific advances in fundamental knowledge and the development of therapies to help reduce risk factors, caries and periodontal disease remain as two of the most dominant oral health issues globally. Currently, approximately 3.5 billion people around the world have experienced at least one form of these diseases in their lifetime.^5,6 Accessible, affordable, and effective interventions that help attenuate the risk of oral diseases are key. Many common oral health conditions are to a great extent preventable and can be reduced through appropriate oral care.^7-9In addition to routine dental exams, daily oral hygiene with a fluoride toothpaste featuring an antimicrobial control agent can provide an important action to help prevent the risk of oral diseases.^10-12

A root cause of many common oral issues is the growth of pathogenic bacteria in the mouth (Figure 1).¹³ Directly or indirectly, these microorganisms can cause damage to hard and soft tissues in the oral cavity, potentially leading to advanced states of disease over time. Bacteria can be present throughout the mouth in planktonic form or within diverse biofilms anchored to an oral surface like the teeth, tongue, cheeks, and gums. If an oral biofilm is left undisturbed, it grows and matures into a biofilm that can be harmful to one's oral health. These mature oral biofilms serve as a safe haven for bacteria and enable them to exchange nutrients, form communication networks with each other to defend against threats, and build structures to resist stress from the environment.^14,15 If these biofilms are not reduced in mass or vitality (and this growth is coupled with additional risk factors favoring disease), they continue to proliferate and a shift in the composition of the microflora may occur that favors pathogenic bacteria.^16-18 An abundance of pathogenic bacteria and their byproducts can be a root cause of many common oral health issues given their ability to release toxins that irritate gums, produce volatile sulfur compounds promoting oral malodor, and generate acids that break down dental hard tissues.

To a certain degree, some oral bacteria and biofilms can be removed through mechanical actions such as brushing with a non-antimicrobial fluoride toothpaste and flossing. However, a lack of consistent compliance to a comprehensive oral hygiene routine can limit the ability of these actions to effectively fight bacteria.¹⁹ Intervention with antimicrobial agents has been clinically proven to reduce oral bioburden significantly by helping control bacteria growth and mitigate bacterial byproducts, even between brushings.^20-22 Antimicrobial agents can also help fight bacteria in areas of the mouth where toothbrushing may be limited, such as interproximally and on soft-tissue surfaces like the buccal mucosa, tongue, and gums. Therefore, targeting bacteria, a root cause of many common oral health issues, with an antimicrobial-based dentifrice provides a more viable route to help in oral disease prevention.

Stannous fluoride (SnF₂) is a well-known active ingredient in dentistry offering multiple oral care benefits.^23-28 SnF₂ offers both hard tissue and soft tissue benefits due to its multiple modes of action. Sn²⁺ ions are known to interfere with bacterial metabolic function, slowing their growth and preventing bacterial acid production.^29,30 SnF₂ has also been shown to form mineral precipitates on dental hard tissues like dentin and enamel.^31,32 These precipitates can occlude exposed dentin tubules, which are a major cause of dentin hypersensitivity. As a result of these diverse modes of action, SnF₂ dentifrices have shown clinically significant reductions in dental plaque formation, gingivitis, malodor, and hypersensitivity pain in addition to prevention of caries and enamel erosion.^28,33,34

While the multiple benefits provided by SnF₂ are a clear advantage to other fluoride sources such as sodium fluoride and sodium monofluorophosphate, which only offer caries protection, SnF₂ dentifrices are challenging to formulate. While relatively inert as a simple salt, SnF₂ dissociates into its constituent ions (F^- and Sn²⁺) in aqueous environments that are common in typical dentifrice formulations.^29,35 Aqueous Sn²⁺ ions are sensitive to air, heat, and water presenting a critical obstacle. Moreover, a dichotomy exists as Sn²⁺ ions are inherently unstable at the optimal conditions for bioactive fluoride. Fluoride ion stability is best in high-water formulations at near neutral or slightly alkaline pH (pH 7-9).^36-38Stannous salts can readily hydrolyze under aqueous conditions, especially above pH 4, resulting in precipitation from solution and/or subsequent oxidation to Sn⁴⁺.^30,39-41

Because clinical efficacy is dependent on the Sn²⁺ state of the ion, it is paramount to try to maintain this oxidation state throughout the lifetime of the product.^29,42-44 If not strategically designed, a SnF₂ dentifrice can run the risk of poor efficacy, surface enamel staining, or a perceivable metallic taste. Even the US Food and Drug Administration (FDA) monograph acknowledges this, stating, "The careful formulation of stannous fluoride dentifrices to prevent rapid oxidation and hydrolysis, and thereby inactivation, of stannous ions is critical for clinical effectiveness of these dentifrices."⁴⁰ A delicate balance must be achieved between maximizing the long-term chemical stability of the active ions in the toothpaste, their potent bioactivity in the mouth, and delivery in a consumer acceptability product form for continued and consistent use. Historically, several different strategies have been pursued in consumer dentifrices. While these mechanisms help address SnF₂ stability and bioactivity, they can impact user acceptability. Taste, mouth feel, and product look can be extremely different in a stabilized SnF₂ toothpaste compared to an ordinary sodium fluoride toothpaste, limiting universal adoption and compliance. Anhydrous formulations can be useful to prevent hydrolysis and subsequent oxidation to the Sn⁴⁺ species but may compromise consumer experience in mouth feel or taste.²⁹ These toothpastes may also exhibit poor standup on a brush and messy textures resulting from a lack of adequate viscosity-building agents that function in low-water formulations.⁴⁵ Some products use additional sources of stannous salts, such as stannous chloride, to compensate for Sn²⁺ ions oxidized or hydrolyzed in the formulation. However, this approach was shown to be inefficient, perpetuating a high level of inactive Sn⁴⁺ ions in the toothpaste.²⁹ This method (like anhydrous formulas) can also lead to high-cost manufacturing or ingredients, limiting affordable options for all users. Chelation with ligands such as pyrophosphate, hexametaphosphate, or organic compounds has proven effective at slowing oxidation, likely through steric complexation mechanisms.^29,32,46 However, complexation mechanisms of Sn²⁺ must be carefully executed, as they may introduce solubility limitations or reduce their bioavailability. In rare cases, SnF₂ toothpastes with complex stabilization systems and limited water content have been implicated in the development of oral discomfort and other localized oral reactions such as oral mucosal exfoliation (Figure 2).^47,48 Given these collective complexities, the consumer products industry devotes significant resources to innovating new ways to optimize a balance of the chemical stability and bioactivity of Sn²⁺ ions in oral care products. However, these complex SnF₂ stabilization mechanisms usually have decreased formula flexibility, limiting major differentiation and innovation between products, such as building in new benefits and/or changes in foam, flavors, and product esthetics.

In 2019, Colgate Total^SF® (Colgate-Palmolive Co., colgatepalmolive.com) was launched in the United States. This formula was comprised of SnF₂ stabilized in a single-phase formulation in the presence of phosphate sources such as tetrasodium pyrophosphate and zinc phosphate in an appropriate organic acid buffer system.²⁹ The toothpaste was formulated at near neutral pH in a high-water (>20%) formulation, helping maintain high levels of fluoride ion stability in the toothpaste matrix. X-ray absorption near edge spectroscopy (XANES) showed the ability of this chelation scheme to maintain higher levels of Sn²⁺ (both free ions and chelated ions) in this toothpaste formulation when compared to other commercially available SnF₂ toothpastes.²⁹ This system was also observed to be highly efficient when normalized to total stannous in the base. Considering the inclusion of only 0.454% SnF₂ in the toothpaste, the ratio of Sn²⁺ to inactive Sn⁴⁺ was 6.63; other commercially available SnF₂ toothpastes (including those supplemented with additional stannous salts) had significant levels of inactive Sn⁴⁺ (40% to 59% of the total stannous in the base) with ratios of less than 1.5.²⁹ Correlation between the Sn²⁺ and Sn⁴⁺ ratios in each product and antibacterial efficacy was observed in vitro.²⁹ Improved stain prevention was also observed with this toothpaste in vitro in assay comparisons to other SnF₂ commercial products highlighting the importance of oxidative stability imparted by the formulation scheme.⁴⁵ Clinical efficacy of this toothpaste has been demonstrated in multiple studies across a broad spectrum of oral health conditions, including reductions in plaque bacteria, gingivitis, and hypersensitivity pain.^31,49,50 The mode of action of the formulation has been examined in clinical studies from bacterial as well as the innate functions of the mouth.^51,52 Specific bacteria, bacterial gene pathways, and oral inflammatory biomarkers influenced by stannous have been identified, concomitantly resulting in healthy biofilm and reduced gingival inflammation.

Recently, researchers discovered that a proprietary combination of phosphates and nitrate ions, two common ingredients in oral care, can help both solubilize and stabilize Sn²⁺ ions in a revolutionary manner.⁵³ These ingredients appear to work synergistically. Pyrophosphate-chelated Sn²⁺ ions maintain this chemistry as a water-soluble, bioactive form at near neutral pH. Simultaneously, nitrate appears to help block the chemical reaction pathways that lead to Sn⁴⁺ conversion, even under conditions known to promote oxidation, including heat, high-water environments, and dissolved oxygen gas. In simple aqueous solutions, this Sn²⁺ active engine showed almost nine times more Sn²⁺ (nearly 90% of starting amount) remaining after 2 weeks at 60°C in comparison to SnF₂ alone (<10% of starting amount remaining).⁵³ This system was also shown in vitro to significantly suppress the growth of known oral disease-causing bacteria (Streptococcus mutans and Porphyromonas gingivalis) and reduce production of the pro-inflammatory cytokine interleukin (IL)-8 in P gingivalislipopolysaccharide-challenged cells.⁵³

Performance testing, including clinical studies, of toothpastes formulated with 0.454% SnF₂ stabilized by nitrate and phosphates have shown impressive results. Application of this engine in various toothpaste backbones has demonstrated the safety, versatility, and high quality associated with this approach. Many of these results are summarized in this special issue, including:

• significant and clinically relevant reductions of bacteria in saliva and on multiple oral surfaces (including teeth, tongue, cheeks, and gums) 12 hours post-brushing after 4 weeks of continuous use⁵⁴

• clinical results showing superior reduction of plaque after 3 months of use; powerful gum care with 100% of patients in a clinical study showing improvement in gingival index over 6 months of continuous use⁵⁵

• significant and clinically relevant reductions in hypersensitivity pain after 1 day (two times brushing) in comparison to a 5% potassium nitrate desensitizing toothpaste⁵⁶

• significant reductions in oral malodor, with 85.7% of patients achieving organoleptic scores corresponding to pleasant breath overnight 12 hours post-brushing after 3 weeks of continued use.⁵⁷

With this active engine, the manufacturer is also able to formulate against key consumer needs associated with lifestyle and environment, including clinically proven tooth stain reduction measured after 3 and 6 weeks of product use.⁵⁸

Finally, this active engine enables an improved pathway to incorporate new benefits and user experiences in a SnF₂ toothpaste. Streamlined and discrete, this technology needs only two ingredients at low levels to ensure SnF₂ stability in a high-water-content toothpaste at near neutral pH, leading to less complexity in manufacturing, fewer flavor restrictions required to mask unfavorable metallic tastes, reduced risk of teeth staining, and decreased toothpaste discoloration. Furthermore, the simple phosphate chelation mechanism used in this engine not only helps limit interactions with a wide variety of formula excipients but also maintains the bioactivity of this active engine upon brushing. The unique combination provides a new opportunity for flexible formulation of a diverse portfolio of efficacious SnF₂-based formulas. In addition to innovation through new benefits and functional ingredients, a wider variety of experiences (foaming profiles, flavors, cooling agents, esthetics) can now be developed to engage and adapt to the diverse preferences of a global population (Figure 3 through Figure 6). In consumer studies, users rated the new toothpaste higher in flavor and foaming attributes (in comparison to the original Colgate Total^SF toothpaste). They also saw the new product as better matched with health-based attributes like "provides long lasting protection for my mouth" and "allows me to be proactive about my oral health."⁵⁷

Colgate's bioactive SnF₂ engine leveraging nitrate and phosphates stabilization technology offers a novel, streamlined, efficacious approach to SnF₂ stability and bioavailability, with distinct advantages, including more efficient manufacturing and enhanced formulation flexibility for broader versatility in flavors, cooling agents, esthetics, and foaming profiles. This novel SnF₂ bioactive engine enables a new, expanded people-centered approach focused on the toothbrushing experience while maintaining multi-benefit efficacy against plaque, gingivitis, cavities, calculus, hypersensitivity, enamel erosion, oral malodor, and tooth staining.

Prevention strategies work most effectively with compliance.^59,60 This engine has also created a unique, new opportunity given its advantages in flavoring, complexity reductions, and resistance to excipient ingredient interactions. Even in a therapeutic toothpaste, the right flavor, foam, color, mouth feel, texture, and cosmetic benefits help to drive compliance. However, different users can have vastly different perceptions and preferences that manifest as reasons to believe or not believe in a product's performance and continued use. The development, customization, and curation of unique experience profiles befitting different groups better promotes consistent use, enabling as many different groups of users as possible to experience the scientific and clinical benefits of a SnF₂ toothpaste.

The author contributions were as follows: LM, CM, RD, and GG: conceptualization, writing original draft; GX: conceptualization, project administration, supervision, resources; YZ: writing, review, and editing; JM: project administration, supervision, resources. All authors contributed to writing, review, and editing.

Research described in this article was funded by Colgate-Palmolive Company. All authors are employees of Colgate-Palmolive Co. CM and GX have patents #US10918580B2 and #US11723846B2 issued to Colgate-Palmolive Co.

The documents containing the results of the research herein described are confidential. The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials.

Lisa M. Manus, PhD
Director Research and Development (R&D), Colgate-Palmolive Co., Piscataway, New Jersey

Carl P. Myers, PhD
Director R&D, Colgate-Palmolive Co., Piscataway, New Jersey

Robert D'Ambrogio, BS
Senior Principal Scientist R&D, Colgate-Palmolive Co., Piscataway, New Jersey

Gokul V. Govindaraju, PhD
Principal Scientist R&D, Colgate-Palmolive Co., Piscataway, New Jersey

Guofeng Xu, PhD
Senior Director R&D, Colgate-Palmolive Co., Piscataway, New Jersey

Yun-Po Zhang, PhD, DDS (Hon)
Senior Vice President and Distinguished Fellow, Clinical Research, Colgate-Palmolive Co., Piscataway, New Jersey

James G. Masters, PhD
Vice President R&D, Colgate-Palmolive Co., Piscataway, New Jersey

Figures and Images

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Figure 6

Figure 1

Fig 1. Oral bacteria can connect as a root cause of many common oral health issues.

Figure 2

Fig 2. Heat map corresponding to the quantity of reported plausible adverse events (AEs) associated with stannous fluoride dentifrices (FDA AEs reporting system [FAERS] public dashboard).48 A = Colgate®, B = Crest®, C = Parodontax™, D = Sensodyne

Figure 3

Fig 3 through Fig 6. A wide variety of esthetics and user experiences (eg, foaming profiles, flavors, cooling agent intensity) can be developed, enabled by the unique advantages of the novel stannous fluoride stabilized by nitrate and phosphates.

Figure 4

Fig 3 through Fig 6. A wide variety of esthetics and user experiences (eg, foaming profiles, flavors, cooling agent intensity) can be developed, enabled by the unique advantages of the novel stannous fluoride stabilized by nitrate and phosphates.

Figure 5

Fig 3 through Fig 6. A wide variety of esthetics and user experiences (eg, foaming profiles, flavors, cooling agent intensity) can be developed, enabled by the unique advantages of the novel stannous fluoride stabilized by nitrate and phosphates.

Figure 6

Fig 3 through Fig 6. A wide variety of esthetics and user experiences (eg, foaming profiles, flavors, cooling agent intensity) can be developed, enabled by the unique advantages of the novel stannous fluoride stabilized by nitrate and phosphates.