THERAPEUTIC DENTIFRICES 817 inhibition of metabolic processes of the oral microorganisms. The develop- ment of a compatible stannous fluoride denrib'ice abrasive system, which was demonstrated to reduce the dental caries rate, was one of the most significant anticaries dentifrice advances (5). Because of the vast amount of laboratory and clinical data on stannous fluoride, the various facets of stannous fluoride and its incorporation into dentifrice formulations will be used to illustrate some of the sequences and interactions operative in the assessment of a thera- peutic denrib'ice. Other fluoride salts will be presented as contrasts when ap- propriate. BACKGROUND A thorough knowledge of the physical and clinical characteristics of the agent as a chemical entity is the basis for all investigations (6). The more complete this knowledge is, the fewer will be the surprises and unfortunate losses of time and effort later. Of particular importance are the reactions of the active ingredient at the conditions of dentifrice manufacture, storage, and use. Essential data are derived from the interaction of the active ingredient with the other ingredients in the dentifrice. With fluoride-containing dentifrices, the primary interaction occurs with the abrasive system, the major (•50%) dentifrice ingredient. Stannous fluoride dissolves easily in water to give acidic solutions (6). Thus, from a solubility viewpoint, it could be used at high concentrations, but the acidic nature of its solutions could cause some immediate formulation and packaging problems. Why not simply neutralize the stannous fluoride solution and eliminate thesc problems? Stability studies examining such variables as pH, concentration, and solution content indicate that stannous fluoride is more stable in a glycerin-containing solution at an acidic pH (6). With hydrolysis of the stannous ion to insoluble hydroxides and reactions of fluoride with ca- tions such as calcium to form insoluble compounds (7), the definition of the formulation restraints are relatively well defined, or at least well enough to make some initial formulation approaches. Needless to say, simple incorpora- tion of stannous fluoride into a chalk dentifrice formulation would be contra- indicated. The chalk (calcium carbonate) system would have a basic pH with easily solubilized calcium to effectively rid the preparation of stannous and fluoride ions (7). Once the best formulations are developed, i.e., formulations with low or no soluble interfering cations and other ingredients compatible to the required somewhat acidic pH (• 4.5), then routine product stability studies are indi- cated. In the case of stannous fluoride, the available stannous and fluoride ion concentrations would be examined as a function of time and temperature. Chemical availability is here defined as the ionic concentration obtained bv preparing a slurry of 1 part paste to 3 parts water (an approximate dentifrice- use concentration ratio). The stannous ion is determined by iodometric titra-

818 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS tion (an oxidation-reduction procedure), rather than by atomic absorption or other methods not distinguishing between tin II and IV, because the stannous ion is more active than the stannic ion (6). The fluoride ion is usually sep- arated by diffusion and determined electrometrically or colorimetrically (6). These analyses will give precise data on the soluble ions chemically avail- able as a function of dentifrice formulation, pH, temperature, and time. It is important to recognize that both stannous and fluoride ions contribute to the anticaries activity (8,9). If a formulation is selected to sacrifice the stannous ions, then sodium fluoride should be chosen as the active ingredient. In fact, the stannous ion does inhibit some of the fluoride from reacting with enamel (8). If the stannous ion stability is of prime concern, why not tie it up in a com- plex which will provide indefinite stability? This situation is not unlike the difference between investing money in a growth situation or placing it in a freeze. Complexes will increase stability, but this may be accomplished at the expense of clinical availability. Thus, a decision must be made in an effort to balance chemical stability and clinical availability. Admittedly the two fac- tors are not mutually exclusive, and chemical instability would result in a lack of clinical availability. Polarography (6, 10) would be the natural laboratory tool to study the strength of complexes. However, such studies would not provide direct information on the availability of the stannous ion to dental enamel. CLINICAL EVALUATION As physical and chemical data are accumulated on fi•e active ingredient alone and in its projected formulations, it is necessary to select methodology to define the clinical availability of the active ingredient to the clinical sub- strate, the tooth. The selection of in vitro and in vivo test methodology to de- fine bioavailability is dependent upon the multiplicity of variables present in the human use situation. No one test should be expected to satisfy the evalua- tion rcquirements of one or several active ingredients in suitable vehicles. The most direct approach to the measurement of stannous and fluoride ion availability from dentifrice formulations to enamel would appear to be ion up- take studies (11). There is very little of this type of data in the published literature. The two main reasons for this situation would appear to be the dif- ficulty of measuring ion uptake from dentifrice slurties under use conditions, ( 12, 13) and the availability of other methods such as enamel solubility tests, •vhich are sensitive to the ion levels in dentifrices. Since the prime mode of dental caries attack is acid dissolution of tooth structure, one of the most frequently used criteria for evaluation of anticaries activity has been the use of enamel solubility reduction (ESR) procedures. The types and modifications of the ESR are extensive. In a review of ESR tests and their significance to dental caries, Brudevold and McCann (14) con-