Differences in Active Agents

The desire to find more effective dentifrices with high compatibility between the fluorie active and different abrasive systems spurred continued research in the development of therapeutic dentifrices. After the success achieved with SnF₂ (Figure 3a) dentifrices, sodium monofluorophosphate (SMFP, Na₂FPO₃ – Figure 3b) new dentifrices were eventually introduced with compatible abrasive systems, and the combinations demonstrated positive caries benefits in most clinical studies. The search for a more stable formulations capable of providing even greater anticaries effectiveness also led to the introduction of a sodium fluoride (NaF – Figure 3c) formulation, which eventually replaced the original stannous fluoride (SnF₂) active ingredient. This new product used the advertising phrase of "Fluoristat" and combined NaF with a silica abrasive system that proved more effective against caries than the earlier "Fluoristan" formulation. This change in active agents occurred in 1981, after silica abrasive systems were developed that were compatible with most of the active agents found in dentifrices.³⁴ All of the fluoride actives have been shown to be successful, to some extent, in preventing dental caries when used in a regular program of oral hygiene. The highly competitive toothpaste market has been a factor in the development of more effective products as well as improving flavor and increasing worldwide usage. This has been a great benefit to public dental health, as evidenced by the decline in the prevalence of dental caries over the past several decades in most developed countries.³⁵

Figure 3a.

Figure 3a.

Stannous fluoride
molecule

Figure 3b.

Figure 3b.

Sodium monofluorophosphate molecule

Figure 3c.

Figure 3c.

Sodium fluoride molecule

The predominance of NaF and Na₂FPO₃ as the active agents in most toothpastes also led to the inevitable question “Are all fluoride dentifrices the same?” This question was addressed by Stookey in 1985 after a review of over 140 articles on fluoride dentifrices.⁸ It was found that a number of dentifrices with various active ingredients (NaF, SnF₂, AmF and Na₂FPO₃) and abrasive system combinations provided significant cariostatic benefits. The major fluoride sources approved for use in the US are stannous fluoride (SnF₂), sodium fluoride (NaF) and sodium monofluorophosphate (Na₂FPO₃). During use, NaF and SnF₂ dissociate to provide the free fluoride ion and the companion cation. The Sn cation may have some interactions on it own, although the primary effects on caries are generally associated with the fluoride component. For Na₂FPO₃, the fluoride source is in a different chemical form and requires enzymatic hydrolysis cleave the covalent bond between the phosphate molecule and fluoride.Studies of SMFP have shown it is compatible with a broader range of dentifrice abrasives, but it may differ in its mode of action from the fluoride ion. Early work suggested that Na₂FPO₃ could react with the apatite surface and reduce dissolution, and it was thought to be retained in the oral environment as the whole molecule.³⁶ Later, studies by Pearce and More³⁷ were unable to confirm this mechanism; and it was felt that most of the activity of this agent was due to fluoride ion present as an impurity. Unfortunately, most studies were not designed to test these active ingredients in head-to-head comparative clinical trials, since they contained different abrasives and levels of fluoride. In his review of the available data, Dr. Stookey⁸ did make several observations. He stated that SMFP formulations gave comparable results to the old SnF₂ dentifrices, and that NaF dentifrices with compatible silica abrasive systems were better in reducing caries than the original SnF₂ products. Four out of five clinical trials demonstrated numerically greater effectiveness for the sodium fluoride product over the monofluorophosphate dentifrices tested. Many in vitro (laboratory) studies also suggested better results for the NaF dentifrices, although some of those studies lacked the presence of enzymes thought to be necessary to break the monofluorophosphate bond and release the fluoride. Although the weight of evidence was obvious in this review,⁸ this question proved to be difficult to answer to everyone’s satisfaction. At that time, the majority of dentifrices sold in over-the-counter products contained either NaF or Na₂FPO₃.

The availability of primarily two active agents naturally resulted in the desire to directly compare these two fluoride actives. Duckworth,³⁸ for example, showed significantly more fluoride was found in plaque from subjects using NaF dentifrices than those using Na₂FPO₃ dentifrices with compatible abrasive systems. To help settle the question, head-to-head clinical trials were needed to clearly distinguish between these products. An in-depth review published in Caries Research (1993) assessed results from essentially every caries clinical trial that directly compared the effectiveness of these two anticaries actives. This review concluded that NaF dentifrices perform better than Na₂FPO₃ dentifrices when using compatible abrasive systems.³⁹ The mean difference in caries reduction between products is approximately 6%, as determined by meta-analysis of the available clinical studies.⁴⁰ However, this same conclusion was not reached in a separate review that assessed the same clinical trials. Although this second review also found that a numerical difference exists that favors NaF over Na₂FPO₃, the authors of this review determined that the magnitude of the difference was not significant.⁴¹ A third review had the benefit of some additional large scale, head-to-head, clinical trials. Similar to the first review, this review also concluded there was a significant advantage to using NaF toothpaste when formulated with a suitable abrasive system.⁴² The new head-to-head comparisons (Marks et al.⁴³ and Stephen et al.⁴⁴) both reported superiority for sodium fluoride over sodium monofluorophosphate dentifrice formulations. The clinical difference between the two products is likely to be due to oral clearance, uptake of fluoride into the enamel and enhanced bioavailability of fluoride in the NaF formulations. In this regard, a properly formulated NaF dentifrice has the greater potential to deliver anticaries benefits, since it will release the fluoride active into the oral environment more efficiently (ionic F release) than from an SMFP formulated dentifrice (requires enzymatic cleavage of the covalent bond to release F^-). Collectively, the evidence from these studies showed NaF dentifrices formulated with highly compatible silica abrasive systems gave significantly better results.