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J Am Dent Assoc, Vol 135, No 2, 231-237.
© 2004 American Dental Association
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ADVANCES IN DENTAL PRODUCTS

The remineralizing effect of an essential oil fluoride mouthrinse in an intraoral caries test



D.T. ZERO, D.D.S., M.S., J.Z. ZHANG, Ph.D., D.S. HARPER, Ph.D., M. WU, Dr.P.H., S. KELLY, J. WASKOW, D.D.S., M.S. and M. HOFFMAN, M.S.


   ABSTRACT
TOP
 ABSTRACT
METHODS, MATERIALS AND SUBJECTS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background. The authors conducted a two-week clinical study to determine the remineralizing effect of an experimental mouthrinse containing both fluoride and essential oils in an intraoral caries test model.

Methods. The study used an observer-blinded, randomized, controlled, 3 x 3 crossover design. The authors enrolled in the study 153 subjects, each of whom had a mandibular removable partial denture. Two partially demineralized human enamel specimens were mounted on each subject’s removable partial denture. Subjects used either a fluoride mouthrinse with essential oils (the test mouthrinse), a fluoride nonessential oils mouthrinse (the positive control) or an essential oil nonfluoride mouthrinse (the negative control) twice daily for 14 days. The researchers assessed specimens for mineral content change and fluoride uptake using surface microhardness, or SMH, testing and enamel fluoride analysis, respectively.

Results. Of the 153 subjects enrolled in the study, 125 subjects were evaluable at the study endpoint. The results after two weeks showed that percentage of SMH recovery was 42 percent in the test group, 36 percent in the positive control group and 16 percent in the negative control group. The fluoride uptake was 19 micrograms per square centimeter, 16 µg/cm2 and 3 µg/cm2 for the test mouthrinse, positive control and negative control groups, respectively. In terms of both percentage of SMH and fluoride uptake, the test mouthrinse and positive control mouthrinse were statistically higher than the negative control mouthrinse, and the test mouthrinse was "at least as good as" the positive control mouthrinse.

Conclusions. This study provides evidence that an essential oil mouthrinse with 100 parts per million fluoride is effective in promoting enamel remineralization and fluoride uptake.

Clinical Implications. The combination of fluoride and essential oils in a mouthrinse may provide anticaries efficacy, in addition to essential oils’ previously established antigingivitis efficacy.

Dental caries and gingivitis, the precursor of periodontal disease, are two major oral diseases affecting large patient populations worldwide. Self-administration of mouthrinses by the consumer is a particularly desirable and appealing delivery method to aid in the treatment of these two diseases, because it is relatively simple and allows a wide margin of variation for safety.1 It has been well-documented that the addition of 100 to 226 parts per million, or ppm, fluoride ions (from sodium fluoride, or NaF) to mouthrinse can significantly reduce or even reverse the initiation and progression of dental caries.1–4 Meanwhile, antimicrobial mouthrinses, including mouthrinses containing a fixed combination of antiseptic essential oils, have been shown effective in controlling plaque accumulation and in helping to reduce gingivitis.5,6 Therefore, the combination of these antiplaque/antigingivitis and anticaries therapies logically would provide patients with more comprehensive and convenient oral care.

The combination of fluoride and essential oils in a mouthrinse may provide anticaries efficacy.

Fluoride’s anticaries efficacy may be affected by several factors, such as fluoride concentration, pH, treatment frequency, dosing volume, treatment time or addition of an antimicrobial agent. We designed a study to compare the overall remineralization effectiveness of an acidic test mouthrinse (containing 100 ppm fluoride and a fixed combination of essential oils) using a dosing regimen of 20 milliliters for 30 seconds, twice daily, with a neutral NaF positive control mouthrinse (containing 100 ppm fluoride) using a dosing regimen of 10 mL for 60 seconds, twice daily. We used an essential oil–containing mouthrinse without fluoride as an anticaries negative control. This study used a modification of the intraoral caries test, or ICT, model,7 also called an intraoral appliance model, as described by Zero,8 with enamel remineralization as an indicator of anticaries activity. We assessed treatment efficacy using as our outcome measures the gauges of percentage of surface microhardness, or SMH, recovery and fluoride uptake in incipient enamel lesions.

Since subjects used their own partial dentures, subject compliance was easily achievable and no excessive discomfort was recorded.


   METHODS, MATERIALS AND SUBJECTS
TOP
 ABSTRACT
 METHODS, MATERIALS AND SUBJECTS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Study design. Our observer-blinded, randomized, controlled, 3 x 3 crossover study used an ICT remineralization model to assess mineral content change (as percentage of SMH recovery) and fluoride uptake (in micrograms of fluoride per square centimeter) in artificially induced incipient enamel lesions. Each subject served as his or her own control.

Test materials and test regimens. We used three test materials and devised three dosing regimens. Each mouthrinse was used twice daily for 14 days. All three mouthrinses were manufactured by Pfizer (Morris Plains, N.J.).

Essential oil with fluoride, or EOF, test regimen. This regimen involved use of an experimental mouthrinse containing 100 ppm fluoride (in the form of NaF) and four essential oils—0.064 percent thymol, 0.092 percent eucalyptol, 0.060 percent methyl salicylate and 0.042 percent menthol, pH = 4.2—as found in Listerine Antiseptic Mouthrinse (Pfizer). This mouthrinse was used at a dose of 20 mL for 30 seconds.

Sodium fluoride positive control regimen. This regimen involved use of a neutral NaF mouthrinse containing 100 ppm fluoride, used at a dose of 10 mL for 60 seconds.

Essential oil-containing negative control regimen. The third regimen involved use of an essential oil–, or EO–, containing mouthrinse without fluoride (FreshBurst Listerine Antiseptic, Pfizer). The oils in this product are 0.064 percent thymol, 0.092 percent eucalyptol, 0.060 percent methyl salicylate and 0.042 percent menthol; the pH is 4.2. This rinse was used at a dose of 20 mL for 30 seconds.

Subjects. Following a protocol reviewed and approved by the institutional review board of Indiana University, Indianapolis, we recruited subjects from communities in the Indianapolis area with a fluoridated water supply (1 ppm F–). Subjects were 18 years of age or older, were in good oral and general health, and provided written informed consent and medical history information. Subjects were required to have a mandibular removable partial denture with sufficient room in the posterior buccal flange area to accommodate two enamel specimens. We enrolled a total of 153 subjects, of whom 152 subjects were randomized, and 125 evaluable subjects completed the study.

Intraoral model. The study used a modified in situ remineralization model by Zero,8 in which clinical personnel of the Indiana University School of Dentistry Oral Health Research Institute, or OHRI, placed enamel specimens on mandibular removable partial dentures. After grinding a 10 x 6 x 2-millimeter space on the acrylic area of the partial denture, the researchers mounted two partially demineralized human enamel specimens on the buccal flange area of the appliance. Since subjects used their own partial dentures, subject compliance was easily achievable and no excessive discomfort was recorded. To simulate the interproximal areas and pits and fissures, where plaque accumulation is present consistently and ion diffusion is restricted, the researchers covered the enamel specimens with gauze (Polyester Knit Fabric, Impra, Tempe, Ariz.). They then luted the enamel specimens in place using a light-cured dental composite (Triad VLC, Dentsply International, York, Pa.). They mounted the specimens in such a manner that the enamel surface of the specimen was flush with the surface of the buccal flange of the denture.

Enamel specimens. Specimens obtained from extracted human permanent teeth were used as the hard tissue test substrate in this in situ caries model. Teeth were free of carious lesions, major restorations, discoloration or cracks, and had sufficient tooth surface to provide a specimen of sufficient size. All grinding and polishing was done under a steady stream of deionized water, which was used for cooling the specimens.

All laboratory procedures were performed by OHRI laboratory personnel. They made longitudinal sections approximately 3 mm in thickness parallel to the selected tooth surfaces using a precision saw (Ultraslice 2000, Ultratec Manufacturing, Santa Ana, Calif.). They then cut tooth sections into 4 x 4-mm blocks using a low-speed saw (Isomet, Buehler, Lake Bluff, Ill.). They ground and polished each specimen on a grinding/polishing machine (RotoPol31/RotoForce 4, Struers, Westlake, Ohio) to create a flat surface to facilitate SMH testing. Specimens had a thickness of no less than 1.8 mm and no more than 2.2 mm.

Surface microhardness analysis. The laboratory staff quantitatively assessed changes in the mineral content of enamel specimens by SMH testing using a hardness tester (Leitz Miniload 2, MeBtechnik GmbH, Wetzlar, Germany) equipped with a knoop indenter. We secured each enamel specimen with sticky wax on a 1-inch-square plastic block and then mounted it on the microhardness tester. We determined the SMH by measuring the length (in micrometers) of the indentations using an image analysis system (Costar CVM 2/3-inch CCD 640 x 480-pixel resolution monochrome video camera, interfaced with the Leitz Miniload 2 Hardness Tester, Optimas Imaging System software, Version 6.1, Upstate Technical Equipment, Syracuse, N.Y.).

The laboratory staff placed five baseline indentations (B1-B5) spaced 100 µm apart with a knoop diamond under a 50-gram load in the center of each flattened, polished sound enamel specimen. They then partially demineralized the enamel specimens using a modification of the method described by White.9 After in vitro demineralization, they again tested the enamel specimens for SMH by placing five indentations (d1-d5) 100 µm directly below the baseline indentations. After sterilization by exposure to ethylene oxide gas, the enamel specimens were mounted on the subjects’ partial dentures. After 14 days of intraoral exposure, the enamel specimens were removed from the partial dentures. The laboratory staff cleaned them and tested them for SMH once more by placing five indentations (R1-R5) 100 µm directly above the baseline indentations.

Using the approach of Gelhard and colleagues,10 we calculated the extent of remineralization for each enamel specimen thus:


We calculated the mean percentage of SMH recovery within each enamel specimen, and we computed the mean percentage of SMH recovery over the two enamel specimens within each subject.

Enamel fluoride uptake. After SMH analysis, the laboratory staff analyzed the enamel specimens for fluoride content using microdrill biopsy.11 They drilled each enamel specimen to approximately 100 µm with a carbide dental bur. They drilled four microholes on each enamel specimen and pooled the enamel powder into one polypropylene vial cap, which served as a microdish for fluoride analysis. They dissolved the enamel powder in perchloric acid solution and analyzed it using a calibrated fluoride electrode immediately after drilling. The researchers then measured the diameter of each drill hole using an eyepiece micrometer and calculated the total area of the four sample holes; the amount of fluoride in each enamel specimen was expressed as micrograms of fluoride per square centimeter.

Clinical protocol. In this three-way crossover study, each treatment period lasted for 14 days. OHRI clinical personnel supervised treatment rinsing in the morning on weekdays to ensure that the correct volume and duration of the rinse was correct; rinsing was unsupervised on weekday evenings, weekends and holidays. During each treatment period, we instructed subjects to use a nonfluoride toothpaste (provided by the sponsor) to standardize their "fluoride background." We also instructed them to wear their partial dentures continuously except during the brushing of their natural teeth.

Before the initiation of each treatment phase, there was a two- to three-day "lead-in" period. During this period, subjects used the test rinse for the immediately ensuing treatment period as directed, but without supervision and without enamel specimens in position. After the first and second treatment phase, there was a washout period of at least four days between the end of a given treatment period and the start of the next lead-in period. During the washout period, subjects resumed their normal oral hygiene practices with fluoridated toothpaste.

Statistical analysis. The primary efficacy variable was percentage of SMH recovery. The secondary efficacy variable was enamel fluoride uptake. For each of the primary and secondary efficacy variables, we tested between-treatment differences using a mixed model with sequence, treatment, period and carry-over as fixed effects, and with subject as a random effect.

For the EOF test rinse regimen to be considered "at least as good as" the NaF positive control in promoting enamel remineralization, we determined that it had to meet the following criteria:

– the mean percentage of SMH recovery for the EOF test had to be statistically significantly greater than the mean percentage of SMH recovery for the EO negative control, on the basis of a two-sided .05 level test;
– for percentage SMH recovery, the lower limit of the one-sided 97.5 percent confidence interval for the difference between the EOF test and NaF positive control means had to be higher than –20 percent of the NaF positive control mean.12,13

We determined that the study could be considered validated if it met these criteria:

– the percentage of SMH recovery for the NaF positive control was statistically significantly greater than percentage of SMH recovery for the EO rinse negative control;
– the difference in mean percentage of SMH recovery for these two groups was at least 10 units (percentage of SMH)—for instance, if the negative control rinse exhibited a 15 percent SMH recovery, the positive control needed to exhibit a 25 percent SMH recovery or greater. On the basis of the findings of Zero,8 we expected the 10 percent difference in SMH recovery between the fluoride treatment and the negative control.


   RESULTS
TOP
 ABSTRACT
 METHODS, MATERIALS AND SUBJECTS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Figures 1Go and 2Go illustrate the mean percentages of SMH recovery and fluoride uptake for all three treatment groups. All three treatment groups exhibited increased SMH (and therefore increased enamel mineral content) relative to their pretreatment values. The mean percentages of SMH recovery from the two treatment groups that used fluoride-containing products were statistically higher than was that from the negative control group, which used a nonfluoridated product (P < .001); thus, the study was valid. The lower one-sided 97.5 percent confidence interval for the difference in mean percentage of SMH recovery and fluoride uptake, expressed as percentage of positive control mean, between the EOF test rinse and the NaF positive control rinse was 5.9 percent and 9.3 percent, respectively, greater than the defined lower limit of –20 percent. This indicated that the EOF test rinse was "at least as good as" the NaF positive control.



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  		Figure 1. A comparison of the percentages of surface microhardness, or SMH, recovery of three regimens: essential oil, or EO, mouthrinse; essential oil fluoride, or EOF, mouthrinse; and neutral sodium fluoride, or NaF, mouthrinse.

 


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  		Figure 2. Comparison of the fluoride uptake (in micrograms per square centimeter, or µg/cm2) of three test regimens: essential oil, or EO, mouthrinse; essential oil fluoride, or EOF, mouthrinse; and neutral sodium fluoride, or NaF, mouthrinse.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS, MATERIALS AND SUBJECTS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
The ICT model used in this study is based on the original design that Koulourides and colleagues7 developed to study fluoride-enamel interactions. The intent of this model system was to mimic the natural caries process and to provide clinically relevant information of anticaries efficacy of fluoride-containing dentifrices and mouthrinses. As such, the method provides a basis for surrogate markers for long-term human clinical studies. Reviews of ICT models and their application can be found in the Proceedings of Workshop on Technological Advances in Intraoral Model Systems Used to Assess Cariogenicity14 and the Proceedings of the Models Conference 1994.15
The differences in both the composition and the dosage regimen of the test fluoride-containing mouthrinse did not adversely affect its ability to promote fluoride uptake and enamel remineralization.

Most previous in situ studies have been limited to between five and 40 subjects, mainly because of logistical demands placed by the clinical and analytical aspects of this type of study. To achieve the statistical power required by the statistical success criteria in this in situ study, we needed 114 evaluable subjects. We enrolled 153 subjects and completed the study with 125 evaluable subjects. We monitored subjects’ compliance closely by weighing returned products and by having the subjects keep rinse logbooks.

The results of this study indicate that the study was valid (that is, that the positive control exhibited remineralization and fluoride uptake far in excess of the fluoride-free negative control), and that the test regimen was "at least as good as" the positive control regimen, which was compliant with the U.S. Food and Drug Administration’s 2003 monograph on anticaries drug products for over-the-counter human use.16 Thus, the differences in both the composition and the dosage regimen of the test fluoride-containing mouthrinse did not adversely affect its ability to promote fluoride uptake and enamel remineralization in the ICT model. The percentage of SMH recovery for the negative control regimen was in the range of that of the negative control treatments in previous dentifrice studies (cited in Zero8), while the two fluoride-containing rinses had percentage of SMH recovery in the range observed for 1,100-ppm dentifrices in previous ICT dentifrice studies (cited in Zero8). Since the enamel specimens were demineralized before the treatment, and subjects were recruited from communities with a fluoridated water supply (1 ppm fluoride), it was not surprising to observe measurable remineralization (15.6 percent SMH recovery) and fluoride (3 µg/cm2) uptake even in the negative control group.

Though studies of fluoride mouthrinses generally have been conducted using formulations with 0.05 percent NaF (226 ppm F–) or higher fluoride concentration using once-weekly or once-daily administration,4,17–19 there have been several publications reporting a positive therapeutic effect of 100-ppm fluoride rinses with twice-daily administration.1,3,20–22 Finn and colleagues’1 clinical study in 1975 compared the cariostatic effectiveness of two acidulated phosphate fluoride rinses that contained either 100 ppm or 226 ppm of fluoride ion and were used twice daily; they found that both fluoride rinses exhibited a cariostatic benefit with no statistically significant differences in the percentage of incremental decayed, missing and filled surfaces between two rinses after 26 months. Since the low concentration of fluoride retained in the mouth after each rinse is the primary action of the anticaries effect,23 the frequency of fluoride exposure can be an important factor on the cariostatic efficacy. The twice-daily use of a 100-ppm rinse therefore could be advantageous over the once-daily use of a 226-ppm rinse owing to more frequent fluoride exposure.

In addition to Finn and colleagues’ human clinical caries trial, Teranaka and Koulourides24 demonstrated the cariostatic effect of a 100-ppm fluoride mouthrinse on experimental root caries using an ICT model. In our study, the two 100-ppm fluoride rinses were evaluated using enamel fluoride uptake and SMH. The greater SMH recovery of 36 percent and 42 percent for the two fluoride rinses relative to the SMH recovery of 16 percent for the fluoride negative control, and the increase of fluoride uptake from 3 µg/cm2 for the nonfluoride rinse versus the 16 µg/cm2 and 19 µg/cm2 for the fluoride rinses, demonstrated the strong remineralization effectiveness of the 100-ppm fluoride rinses.

The dosing in the EOF test regimen and the NaF positive control regimen differed in both volume and duration. Theoretically, larger rinsing volume from the test regimen may reduce the dilution factor by the saliva and increase the cariostatic efficacy, while the longer duration for the positive control may increase fluoride’s penetration into enamel. However, the clinical impact of volume and duration differences was not measurable. The results from our study demonstrate that an essential oil–containing antiseptic mouthrinse containing 100 ppm of fluoride ion, used in a twice-daily 20-mL, 30-second rinsing regimen, has effects comparable with those of NaF mouthrinse regimens currently approved in the FDA Anticaries Final Monograph.16

In vitro studies have shown that the fluoride uptake from acidic phosphate fluoride solutions (pH < 4) was high in the surface layer of the enamel.25–27 The mechanism of action of increased fluoride uptake by acidulated fluoride mouthrinses could be due to an increase of hydrogen fluoride concentration, increase of diffusion rate,28 increase of precipitation of calcium fluoride on the surface that serves as a fluoride reservoir29 and change of enamel surface charge. However, the differences of the remineralization effect between the neutral pH rinse and the acidic rinse were not great in clinical studies, owing to the strong buffer capacity of plaque fluid and saliva.1–3,21 In our clinical study, the weakly buffered acidic test rinse (pH = 4.2) had only a slight advantage in terms of fluoride uptake and SMH recovery over the neutral pH NaF positive control rinse.


   CONCLUSION
TOP
 ABSTRACT
 METHODS, MATERIALS AND SUBJECTS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
On the basis of our in situ study, we conclude that an essential oil mouthrinse with 100 ppm fluoride is effective in promoting enamel remineralization and fluoride uptake in incipient lesions. Our findings suggest that the combination of fluoride and essential oils in a mouthrinse may provide anticaries efficacy, in addition to essential oils’ previously established antigingivitis efficacy.


   FOOTNOTES
 

Dr. Zero is the associate dean for research; a professor and the chair, Department of Preventive and Community Dentistry; and the director, Oral Health Research Institute, all at Indiana University School of Dentistry, 415 Lansing St., Indianapolis, Ind. 46202, e-mail "dzero{at}iupui.edu". Address reprint requests to Dr. Zero.


Dr. Zhang is the senior scientist and study monitor, Pfizer Consumer Healthcare Research and Development, Pfizer, Morris Plains, N.J.


Dr. Harper is the associate director and project leader, Pfizer Consumer Healthcare Research and Development, Pfizer, Morris Plains, N.J.


Dr. Wu is the senior manager, Statistics, Pfizer Consumer Healthcare Research and Development, Pfizer, Morris Plains, N.J.


Ms. Kelly is the associate director, Clinical Research Facility, Oral Health Research Institute, Indiana University School of Dentistry Indianapolis.


Dr. Waskow is an assistant professor, Department of Preventive and Community Dentistry, Indiana University School of Dentistry, Indianapolis.


Mr. Hoffman is the laboratory manager, Oral Health Research Institute, Indiana University School of Dentistry, Indianapolis.


The study described in this article was supported by Pfizer, Morris Plains, N.J.


   REFERENCES
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 ABSTRACT
 METHODS, MATERIALS AND SUBJECTS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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