816 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS caries occurs. This carions process is not a generalized process but one re- stricted to specific tooth sites. At other sites, often on the same tooth, mineral- ization may be favored. Tooth mortality studies in Sweden (1) have indicated that dental caries is the cause for 75% of the tooth extractions occurring in the first 25 years of life. After 50 years of age, tooth Koss due to soft tissue (periodontal) disease becomes more significant, but even then dental caries remains a maior cause of tooth loss. Dental caries is probably not a single disease entity. Socransky (2) has listed four types of dental caries differentiating them on the basis of the specific site of activity and the microorganisms present at the site, i.e., smooth surface, pit and fissure, root surface (cementum), and deep dentin caries. Smooth surface dental caries requires dental plaque with good adhesive prop- erties. A few strains of streptococci produce this adhesive dextran plaque from sucrose. Pit and fissure dental caries occurs when acid-producing micro- organisms are packed into the tooth crevices. These crevices are located pri- marily on the occlusal or chewing surfaces of the teeth and thus the term oc- clusal caries is frequently used. These microorganisms have a less specific biochemical character, and because of the protective shelter of the tooth crevice they do not require plaque for adhesion to the tooth surfaces. Dental caries occurring on the root surfaces of teeth afflicted with periodontal disease may be a by-product of a somewhat different, mildly acidiogenic group of microorganisms common to the gingival crevice area. The fourth type of den- tal caries, deep dentin caries, may be caused by microorganisms different from those initiating the lesion in the enamel surface. In the design of an anticaries agent, there would appear to be a number of routes and points of attack. Some of these general approaches might include: antibacterial, antibacterial metabolite, substrate (tooth structure) alteration, fluid phase (saliva) alteration, and diet control. Many of these approaches and their ramifications have been reviewed previously (3). At present, sub- strate alteration is most important and successful in retardation of the dental caries process. Although physical protection of the tooth surface with the use of a sealant on the occlusal surface has enjoyed some success (4), improve- ment of the chemical resistance to dissolution is most important. Dietary fluoride through communal fiuoridation is the most effective and efficient route to the reduction of dental caries (5). The dietary fluoride is incorporated into the tooth structure at the time of mineralization and effec- tively produces a more perfect structure. Subsequent topical administration of fluoride at substantially higher concentrations (dentifrice-0.1% fluoride, and professionally applied preparations-l.2 to 10% fluoride) supplement the dietary fluoride. It should be recognized that the prime site for fluoride activity is the tooth mineral. However, the effect of fluoride in some vehicles may be due in part to

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-