Vol. XXVI, No. 2 The Journal of Clinical Dentistry 45

Erosion Prevention Potential of an Over-the-Counter Stabilized SnF 2 Dentifrice Compared to 5000 ppm F Prescription-Strength Products S.L. Eversole, AAS K. Saunders-Burkhardt The Procter & Gamble Company Cincinnati, OH, USA R.V. Faller, BS Maurice H. Kornberg School of Dentistry Philadelphia, PA, USA Abstract Objective: To determine the relative ability of various F-containing products to protect enamel against the initiation and progression of tooth surface loss due to erosive acid challenges. Methods: Cores of enamel were prepared from extracted human teeth, soaked in pooled human saliva (pellicle formation), and then treated in a 1:3 slurry (product:saliva) of either OTC level (1100 ppm F) or prescription level (5000 ppm F) products, followed by a standardized erosion cycling procedure (five days of cycling) that included 10-minute challenges with an erosive dietary acid (1% citric acid at ph 2.3) applied 60 minutes after each dentifrice treatment (repeated four times per day). Enamel surface loss was measured using transverse microradiography. Two studies were conducted. Study 1 included: A) 1100 ppm F as NaF; B) 1100 ppm F as stabilized SnF 2 ; C) 5000 ppm F as NaF; and D) 5000 ppm F as NaF + acidulated phosphate. Study 2 included: 1) 1100 ppm F as stabilized SnF 2 ; 2) 5000 ppm F as NaF + tricalcium phosphate; and 3) 1100 ppm F as NaF. Results: Study 1: Treatment B (1100 ppm F as SnF 2 ), where specimens lost only 8.0 µm of the enamel surface, was significantly more effective than Treatments A, C, and D at protecting enamel against the initiation and progression of erosive acid damage (p < 0.05). Specimens treated with product A exhibited 22.8 (1.25) µm (mean ± sem) of enamel loss; 20.0 (0.71) µm of enamel loss with treatment C and 24.0 (1.4) µm of enamel loss with Treatment D. Study 2 also demonstrated significantly greater erosion protection with the stabilized SnF 2 dentifrice (p < 0.05), with only 5.8 (1.93) µm of tooth surface loss, while groups 2 and 3 lost 19.8 (0.75) µm and 18.0 (2.16) µm, respectively. Conclusion: Results from both studies demonstrated the OTC dentifrice formulated with stabilized SnF 2 provides significantly greater protection against erosive acid attack compared to some of the most popular prescription level (5000 ppm F) fluoride treatments available. (J Clin Dent 2015;26:44 49) Introduction Although the initial process related to both caries and dental erosion begins with teeth being subjected to acid attack, the subsequent stages of each process are quite distinct. For example, dental erosion is a process that generally initiates on facial surfaces of teeth on which plaque is not present, while caries occur under plaque coated surfaces, where relatively constant, low level acid challenges penetrate through the surface of the teeth and create subsurface lesions while allowing the surface to remain intact in the early stages of development. 1,2 In the case of dental erosion, excessive exposure to dietary acids causes the pellicle, the natural protective film present on exposed tooth surfaces, to be overwhelmed. The exposed surfaces of the teeth then begin to soften. 1 Once softened, these surfaces have been shown to be highly susceptible to tooth surface loss. 1,3,4 Although some studies have suggested this softened layer can be partially rehardened, particularly in the laboratory, once surface loss starts there is no information available that would suggest that this lost mineral can be restored in vivo. 5 As such, dental erosion is generally considered a condition of irreversible tooth surface loss. 6 Fluoride has long been recognized for its ability to promote remineralization and help prevent demineralization of tooth surfaces subjected to acids related to the caries process. 7-11 For this reason, fluoride has been an obvious candidate for assessing its potential 44 to aid in the prevention of dental erosion. 5 Although most researchers agree that the more commonly used fluorides, such as sodium fluoride and sodium monofluorophosphate, are able to strengthen the enamel through remineralization processes, there is growing concern that remineralization by fluoride alone does not provide a sufficient level of protection to help prevent the initiation and progression of dental erosion. In fact, a number of studies have demonstrated that many of the currently available fluoride-containing products provide only minimal protection against dietary acid challenges. 5,12-16 This is important, because other studies have demonstrated that consumer habits have changed dramatically over the past few decades. This change has resulted in significantly greater acid challenges, in the form of excessive intake of acid-containing beverages, that carry the potential to dramatically increase erosive tooth surface loss unless solutions can be identified that provide higher levels of acid protection. 1 One exception to the lack of erosion protection performance for many of the currently available F-containing products is stabilized stannous fluoride (SnF 2 ) dentifrice, which is becoming increasingly recognized for its ability to prevent both the initiation and progression of dental erosion. 12,13,15-21 SnF 2 is a well-established anticaries agent that is unique among the fluoride sources used in overthe-counter dentifrices. In addition to its ability to fight caries, 22,23

Vol. XXVI, No. 2 The Journal of Clinical Dentistry 45 gingivitis, 24,25 and sensitivity, 26-29 dentifrices formulated with SnF 2 have also been confirmed in numerous studies, both in vitro and in human in situ clinical trials, to help prevent the initiation and progression of dental erosion. 12-16,20,21,30,31 Different from other sources of F, SnF 2 deposits an acid-resistant barrier layer onto exposed pellicle-coated tooth surfaces that remains for at least several hours after product use. 18 The retention of this protective barrier layer on treated tooth surfaces appears to be critical for protection against subsequent erosive acid challenges. 17,19 Another possible approach that has been suggested is the use of higher levels of fluoride, such as those found in prescription-level products. There have been a few studies reported in the literature in which products formulated with 5000 ppm F were tested relative to conventional levels of fluoride found in OTC products (1000-1500 ppm F). While two of these studies suggested higher levels of fluoride might provide an enhanced erosion prevention benefit, 32,33 two others failed to demonstrate any difference between the OTC and prescription levels of F with respect to protection against erosive acid challenges. 34,35 To date, there have been no credentialed, erosion cycling model studies published comparing the higher concentration, prescription level F products (5000ppm F) against any dentifrices formulated with stabilized SnF 2. The purpose of the current studies was to compare the effectiveness of the stabilized SnF 2 dentifrice, which has been proven to provide superior erosion protection benefits in both in vitro 12,13,20,21 and human in situ clinical studies, 15,16,31 against three different prescription strength products formulated with 5000 ppm F. One product contained 5000 ppm F as sodium fluoride (NaF), another 5000 ppm F as NaF + acidulated phosphate, which is intended to drive higher levels of F into treated enamel, and the third contained 5000 ppm F as NaF + tricalcium phosphate, an ingredient that is claimed to enhance the mineralization potential of that particular formulation. 36 Materials and Methods The study was conducted according to the guidelines for Good Laboratory Practice (GLP). Human enamel specimens were prepared using standard procedures. 12 Study Design The in vitro erosion cycling model used in the current studies evaluates the relative ability of oral care products to protect tooth surfaces against both the initiation and progression of erosive acid challenges. 12,13,21 Tooth specimens, in groups of four per test cell, are cycled through 20, two-minute treatment cycles over a five-day period. Each group of specimens receives a ten-minute erosive acid challenge one hour after each treatment with the appropriate test product. By including the erosive acid challenge a full hour post product treatment, the model assesses the ability of a test product to be retained on the tooth surface for at least one hour after treatment and still withstand an erosive challenge. When not in treatment or erosive acid challenge, each group of specimens remains in a pooled, human saliva bath to allow replenishment of the protective pellicle layer and simulate a normal oral environment. After each erosive challenge, specimens remain in pooled human saliva for approximately one hour prior to the initiation of the next treatment cycle (Figure 1). Figure 1. Graphical representation of the erosion cycling procedure. Upon completion of the cycling phase, all specimens were crosssectioned and analyzed using transverse microradiography (TMR) software (Inspektor Research Systems BV, Amsterdam, The Netherlands). The mean surface loss is reported for each treatment group as microns of enamel lost. The percent change in surface loss versus the NaF reference control was calculated for each treatment group in each study. Products Evaluated Table I includes a listing of products used in each study. All products were tested well within the expiration dates listed on the individual product packages. In both studies, the erosion protection ability of each test product was measured relative to a standard reference control (Crest Cavity Protection toothpaste, The Procter & Gamble Company, Cincinnati, OH, USA, containing 1100 ppm F as NaF in a silica abrasive system). Key test products included in the studies represent widely used, prescription strength, F-containing products sold commercially in the United States, as well as a stabilized SnF 2 dentifrice that has been demonstrated in multiple in vitro and human in situ clinical studies to provide significant erosion prevention benefits. 12,13,15,16,20,21,30,31 Table I Dentifrice Products Tested Test Group Product Treatment Key Active Ingredient(s) Study 1 A Crest Cavity Protection Toothpaste a 1100 ppm F as NaF B Crest Pro-Health Toothpaste a 1100 ppm F as SnF 2 C Colgate PreviDent Brush-on Gel b 5000 ppm F as NaF D Colgate Phos Flur Gel b 5000 ppm F as NaF + acidulated phosphate Study 2 1 Crest Pro-Health Toothpaste a 1100 ppm F as SnF 2 2 Clinpro 5000 Anticavity Toothpaste c 5000 ppm F as NaF + Tri-calcium phosphate 3 Crest Cavity Protection Toothpaste a 1100 ppm F as NaF a The Procter & Gamble Company, Cincinnati, OH, USA b Colgate-Palmolive Company, Piscataway, NJ, USA c 3M ESPE, St. Paul, MN, USA

46 The Journal of Clinical Dentistry Vol. XXVI, No. 2 Collection of Human Saliva Eight to ten healthy volunteers were recruited to provide human saliva for each study. After saliva samples were collected (early in the morning from each volunteer on each day of the study in order to maintain a relatively constant pool of saliva), the samples were then pooled and refrigerated at approximately 5 C until use (generally within one day). All required precautions were followed to ensure proper handling of saliva from the point of collection to its use in each of the laboratory studies. In order to generate saliva, each volunteer chewed paraffin wax and expectorated the stimulated saliva generated into a plastic collection vessel. The collection period averaged approximately 30 40 minutes per volunteer per collection period. Specimen Collection and Preparation Enamel samples were prepared from extracted human teeth for both studies. The teeth, typically removed for orthodontic reasons, were obtained from local oral surgeons who collected and stored the teeth after extraction. Appropriate precautions were followed to ensure proper handling of tooth samples from the point of extraction to the ultimate use in each of these studies. Each tooth was individually cleaned and checked for any visible surface cracks or other imperfections prior to use, and specimens with any visible imperfections were discarded. Teeth were stored prior to use in a 1% thymol solution. Enamel specimens were prepared by cutting enamel cores from the collected teeth using a diamond core drill. Each specimen was mounted in a ¼ inch diameter Lucite rod using dental acrylic (Durabase, Reliance Manufacturing Company, Worth, IL, USA) covering all sides except the natural facial surface. Specimens were polished with 600 grit silicon carbide-water slurry to remove approximately 50 µm of the outer enamel. Specimens were then polished for an additional 90 minutes with gamma alumina (Linde No. 3, AB Gamma Polishing Alumina, Buehler Limited, Lake Bluff, IL, USA). Any specimen found to have visible surface imperfections was rejected. Following this preparation, nail polish was applied to the surface of each specimen, leaving a treatment window of unprotected enamel approximately 3.0 mm x 0.4 mm (Figure 2). Specimens were randomly assigned to treatment groups of four specimens each. Figure 2. Enamel specimens are mounted individually in lucite rods, which are then placed in a specially designed holder for treatments, 4 specimens per group. The surface of each specimen is covered with acid resistant nail polish, with the exception of a standardized exposure window (approximately 0.4 mm wide) on the surface of each specimen. Daily Cycling Protocol At the initiation of each study, each group of specimens was placed into 20 ml of fresh, pooled human saliva for one hour to encourage the formation of a pellicle layer on the exposed enamel surfaces. Fresh dentifrice treatment slurries were prepared by mixing five grams of dentifrice with 15 grams of fresh, pooled human saliva for a period of between four to five minutes prior to use for each treatment. Each treatment cycle consisted of: dentifrice/saliva slurry (two minutes) rinse in deionized, distilled water (ddih 2 O) pooled, human saliva (one hour) erosion challenge (ten minutes) rinse in ddih 2 O pooled, human saliva (one hour). Each study included four treatments per day for a total of five days of treatment. Dentifrice treatments consisted of immersing the specimens into the dentifrice/saliva slurry for two minutes while specimens were rotated at a constant speed of 75 rpm to provide low levels of shear forces. The erosion challenge consisted of soaking each treatment group in 12 ml of 1% citric acid at neat ph, ~2.3 (at room temperature). When not undergoing treatment, specimens remained in 20 ml of pooled, human saliva that was gently and constantly stirred, again to provide low levels of shear. The saliva was refreshed three times each day. At night, each group of specimens remained immersed in pooled, human saliva that was gently and constantly stirred. Post-treatment Specimen Handling After five days of treatments, each group of specimens was rinsed well in ddih 2 O and stored in a humid environment at approximately 5 C until analysis. Analysis of Specimens All specimens were analyzed for the study using a calibrated, cross-sectional microradiography system that has been found to be particularly well suited for measuring erosive tissue loss in this model system. 12,13,21 Prior to analysis, a layer of nail polish was applied to the entire surface of each specimen to seal the surface and protect the areas that had been exposed to the erosive acid challenges. Specimens were then cut plano-parallel using a hard tissue sectioning saw (Silverstone-Taylor Hard Tissue Microtome, Scientific Fabrications, Littleton, CO, USA). Each section was cut in such a way that both the control and treated portions of the specimen were accessible for analysis. A thin section (~100 µm) was removed from each specimen, placed flat on a specially designed mount that was then fitted to a camera connected to an X-ray generator (Philips Model #PW1830, Philips Analytical, Natick, MA, USA), and exposed to CuKa radiation. Micrographs were taken using Kodak SO253 Holographic film (Eastman Kodak Company, Rochester, NY, USA), which was then processed using standard film developing methods. Radiographic images were analyzed using Transverse Microradiography (TMR), a calibrated, computer-based image analysis system (Inspektor Research Systems BV, Amsterdam, The Netherlands). By comparing the original surface, based on the control (untreated) area to the post-treatment surface, the depth of the eroded area can be directly and accurately measured (µm of mineral lost), as noted in Figure 3. Although a number of analysis techniques are available, for this study the use of TMR was very efficient for the measurement of erosive surface loss. It enabled direct examination, from a cross-

Vol. XXVI, No. 2 The Journal of Clinical Dentistry 47 Study 1 Study 2 Test Group Mean Surface Loss ± SEM (µm) a B 8.00 (1.21) C 20.0 (1.21) A 22.8 (1.21) D 24.0 (1.21) Test Group Table II Results and Statistical Analysis Mean Surface Loss ± SEM (µm) a 1 5.8 (1.73) 3 18.0 (1.73) 2 19.8 (1.73) a Mean ± SEM Means within the same bracket are not statistically significantly different (p < 0.05) using a Bonferroni multiple comparison adjustment Figure 3. Graphical representation of the analysis procedure. a) human enamel specimen after the erosion cycling is complete; b) a thin cross-section of the specimen is removed for X-ray analysis; c) typical radiograph; and d) calculation of surface loss as the difference between the treated and untreated control areas in µm. (Adapted with permission from Faller, et al., 2011 12 ). sectional perspective, of the sound surface and the exposed challenged surfaces in the same image. 12,13,21 Results from this model, as practiced using TMR analyses, have consistently agreed with results of human in situ clinical trials 15,16,31 in which surface profilometry was used (data on file). Statistical Methods A one-way ANOVA followed by post hoc comparisons between the stabilized SnF 2 and each of the other groups was done to control for multiple testing. A Bonferroni multiple comparison adjustment was used for the analysis. Results In each of the two studies, the stabilized SnF 2 dentifrice provided significantly better protection against both the initiation and progression of dental erosion compared to any of the 5000 ppm F (prescription strength) products tested (p < 0.05). Consistent with previous studies, the stabilized SnF 2 dentifrice also performed significantly better than the 1100 ppm F (NaF) control in each study, confirming the reproducibility of the model to demonstrate this proven difference in effectiveness. Results for both studies are presented in Table II, which includes: 1) mean surface loss, or depth of erosion, per treatment group (µm); 2) standard error of the mean (SEM); and 3) results of the statistical analyses of the data. In study 1, specimens treated with the stabilized 1100 ppm F (SnF 2 ) dentifrice lost an average of only 8.0 µm of tooth surface over the course of the study, while those treated with the 1100 ppm F (NaF) reference control lost 22.8 µm. Enamel specimens treated with the 5000 ppm F (NaF) prescription gel exhibited 20.0 µm of tooth surface loss, and those treated with the 5000 ppm F (NaF) + acidulated phosphate gel lost an average of 24.0 µm of enamel, a full three-times greater loss than that measured with the use of the stabilized SnF 2 dentifrice. Study 2 followed similar patterns, with specimens treated with the stabilized 1100 ppm F (SnF 2 ) dentifrice losing only 5.8 µm of enamel, while the average surface loss for specimens treated with the reference control dentifrice was 18.0 µm. Consistent with results from Study 1, specimens treated with the 5000 ppm F (NaF) prescription strength product included in Study 2 lost three times (3X) more enamel than specimens treated with the stabilized SnF 2 dentifrice. In both of the studies presented here, none of the 5000 ppm F (prescription strength) products performed significantly better than the 1100 ppm F (NaF) reference control. Discussion In 2007, Hooper, et al 15 demonstrated, using a human in situ clinical trial, the enhanced protective effects of a stabilized SnF 2 dentifrice against a dietary erosive challenge. In that study, which compared the relative efficacy of the stabilized SnF 2 dentifrice to both an 1100 ppm F (NaF/silica) dentifrice and a water control, the stabilized SnF 2 dentifrice provided a 56% reduction in erosion versus the water control after 15 days of product use and acid challenge, while the 1100 ppm F (NaF) dentifrice provided a benefit of approximately 25%. This study provided clear evidence of the protective nature of SnF 2 against dental erosion. The in situ clinical models of Hooper and others have consistently demonstrated significant erosion protection benefits of stabilized stannous-containing dentifrices. 15,16,30,31 It is not possible to conduct clinical trials on every product of interest. For that reason, properly credentialed in vitro models are useful tools for predicting performance in clinical trials. The in vitro erosion cycling model that has been used in the current studies assesses the potential of oral care products to protect tooth surfaces against not only the initiation, but also the progression of erosive acid damage. The model simulates the key processes occurring in the mouth during erosive acid challenges in an environment that includes human teeth, human saliva, salivary flow, pellicle development, shear forces, routine fluoride exposure, and daily acid challenges. Both of the studies presented here compared the relative effectiveness of the same two F-containing dentifrices that had been included in the human in situ clinical study of Hooper. 15 As in the study by Hooper,

48 The Journal of Clinical Dentistry Vol. XXVI, No. 2 the stabilized SnF 2 dentifrice performed significantly better than the 1100 ppm F (NaF) control in each of the studies presented here. This same model has also demonstrated highly significant differences in the relative ability of a number of marketed products to provide erosion protection benefits. In each study, stabilized stannous-containing dentifrices have repeatedly demonstrated superior protection against erosive acid challenges compared to other fluoride sources, such as NaF, amine fluoride (AmF), sodium monofluorophosphate (SMFP), and combinations of F agents, such as NaF + SMFP, among others. 12,13,21 In addition to once again demonstrating the clinically confirmed superiority of the stabilized SnF 2 dentifrice over the 1100 ppm F (NaF) dentifrice in this model system, both studies also confirmed the superiority of the 1100 ppm F stabilized SnF 2 dentifrice over all of the 5000 ppm F prescription level products tested with respect to their ability to protect tooth surfaces against both the initiation and progression of erosive acid damage. In spite of higher levels of F in the prescription-level products included in the current studies, they were not able to protect the treated tooth surfaces more than the 1100 ppm F (NaF) control. This result suggests that even though higher levels of F are able to provide enhanced anticaries benefits, 37,38 the severity of the challenge present during erosive acid attacks requires a different approach in order to provide a sufficient level of protection against potential damage. While studies have demonstrated that most F-containing products are able to provide at least a measureable level of erosion protection effects, enhanced protection benefits appear to be limited to one specific F agent, stabilized SnF 2. Although F plays two roles in caries-related processes, including both the inhibition of demineralization and the enhancement of remineralization, 39 SnF 2 is unique in its ability to deposit an acid-resistant barrier layer on pellicle-coated tooth surfaces that is highly protective against erosive acid challenges. 17-19 Whereas NaF is believed to provide some level of protective benefit due to the likely formation of calcium fluoride (CaF 2 ) in situ, SnF 2 has been demonstrated to form tinrich complexes that are capable of enhancing the resistance of the tooth surface against acid challenges at a level that is unmatched by CaF 2 precipitates. 5 In combination with F, the polyvalent stannous metal cation has proven to be significantly more effective in reducing erosive acid damage than other fluoride sources in in vitro and in situ studies that have tested both toothpastes 12,13,15,16,20,21,30,31 and rinses. 40,41 One of the most important aspects of the stabilized SnF 2 formulation is its demonstrated ability to deposit onto, and be retained on, pellicle-coated enamel surfaces for several hours after product use. 18 Retention of the stannous-rich barrier layer provides a significant level of protection against erosive acid challenges that is unique among the sources of F routinely found in commercial dentifrices. Even significantly higher levels of a conventional F source, such as the 5000 ppm F level of NaF found in prescription-strength products, was unable to protect tooth surfaces against erosive acid attack in this credentialed model system. Under the conditions of this model, the prescription-level products all provided similar levels of benefit and did not appear to differ in absolute performance, whether the formulation was simply 5000 ppm F as NaF, 5000 ppm F as NaF + acidulated phosphate, or 5000 ppm F as NaF + tricalcium phosphate. This strongly suggests that incorporation of F into the enamel, even at elevated levels in combination with calcium and phosphate to enhance remineralization of the enamel, does not provide as great a protective benefit against erosive acid challenge as the stabilized SnF 2, formulated at conventional OTC levels of fluoride. Conclusion Collectively, the data continue to support both the uniqueness and significantly greater effectiveness of stabilized SnF 2 relative to other popular fluoride products, to protect exposed tooth surfaces against the initiation and progression of dental erosion. Results from both of the current studies demonstrated the stabilized 1100 ppm F (SnF 2 ) OTC dentifrice provides superior protection against erosive acid attack compared to some of the most popular prescription level (5000 ppm F) fluoride treatments available. Acknowledgment: This study was supported by The Procter & Gamble Company. For correspondence with the authors of this paper, contact Sandra L. Eversole eversole.sl@pg.com. References 1. Lussi A, Carvalho TS. Erosive tooth wear: A multifactorial condition of growing concern and increasing knowledge. In: Erosive Tooth Wear: From Diagnosis to Therapy, Lussi A, Ganss C, eds. Karger, Basel pp.1-15, 2014. 2. Ganss C. Is erosive tooth wear an oral disease? 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