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Figure 4 The five tissues of a tooth.

The Periodontium

The periodontium (from the Greek "peri," meaning "around," and "odous," for "tooth") is a functional system consisting of several different tissues that surround and support the teeth. This system is also called the ''attachment apparatus'' or the ''supporting tissues of the teeth.'' Anatomically, the term refers only to the connective tissue between the teeth and their bony sockets (Fig. 5).

The tissues that make up the periodontium include the gingiva, the periodontal ligament, the cementum, and the alveolar bone or jawbone. Their good health is of great importance to the overall health of your mouth and the survival of your teeth.

The Gingiva

The gingiva, commonly called the ''gums,'' is the most external part of the periodontium. It is composed of dense fibrous tissue which forms a close ring-like attachment around the necks of the teeth and connects with the epithelial covering (oral mucosa) that lines the mouth. The gingiva is firm in consistency and does not move from its underlying structures. It is covered by a smooth vascular mucous membrane which is tender to the touch and bleeds easily when penetrated or bruised. It also overlays the unerupted teeth, and the pain which occurs during the teething process is the result of the new tooth pushing through this sensitive tissue. Clinically the gingiva is divided into following:

1. Free marginal gingiva which is about 1.5 mm wide and forms the skin-like soft-tissue fold around the teeth. The narrow shallow groove present between the tooth and the free gingiva is known as the gingival sulcus. It is approximately 0.5 mm deep and 0.15 mm wide and surrounds the tooth on all sides. The bottom of the sulcus is made up of cells from the junctional epithelium. The size of this groove or ''pocket'' is of great importance when determining the health of the periodontium and the stability of the teeth.

Figure 5 A healthy tooth with its periodontium.

Figure 5 A healthy tooth with its periodontium.

2. Attached gingiva which is firmly connected to the hard surface of the tooth by means of a ring of specialized tissue known as the junctional epithelial attachment. The attached gingiva becomes wider with age and may vary considerably among individuals and from tooth to tooth.

3. The cells in the junctional epithelium are continuously being renewed during life and have a turnover rate of every 4 to 6 days. This results in a very permeable tissue which serves as a pathway for the metabolic products produced by the bacteria present in the mouth. This area plays a key role in the maintenance of periodontal health.

4. Interdental gingiva which varies in depth and width and occupies the area between adjacent teeth.

The Periodontal Ligament and the Cementum

The periodontal ligament occupies the space between the root surface of the tooth and the alveolar bone or jawbone. It is composed of connective tissue fibers, blood vessels, nerves and other cells. Its function is to provide the connection between the cementum layer of the tooth and the jawbone, the teeth and the gingiva, and between each tooth and its neighbor. Anatomically the cementum is a part of the tooth, but functionally, it belongs to the tooth-supporting apparatus because the gingival and periodontal ligaments are anchored in it.

The Alveolar Bone

Alveolar bone, also referred to as the jawbone, develops along with the formation of the teeth throughout pregnancy and continues to grow during the eruption of the teeth in childhood. Three types of alveolar bone have been defined: compact bone, trabecular bone, and alveolar bone proper. The trabecular bone provides the major support structure of the teeth and is composed mainly of fatty marrow in adults.

Other Parts of the Mouth

There are several other areas in the mouth which are important. These include the tongue, palate, salivary glands, and the oral mucosa or lining of the mouth or oral cavity itself.

Palate

The palate forms the roof of the mouth and consists of two portions: the hard palate in the front area behind the upper teeth and soft palate at the back at the entrance to the pharynx or throat area. The hard palate separates the mouth from the nasal cavity and serves as the roof of the mouth and the floor of the nose. The soft palate aids in swallowing and sucking functions.

Tongue

The tongue is the main organ of the sense of taste and an important organ of speech. It also assists the teeth in the chewing and swallowing of food. The tongue is situated in the floor of the mouth and is connected to various muscles in the epiglottis and pharynx, or throat. It is covered by mucous membranes, and numerous mucous and serous glands as well as taste-buds. Internally, it consists of fibrous tissue, muscles, blood vessels and nerves (Fig. 6).

Figure 6 The anatomical location of the palate and tongue within the oral cavity.

Saliva and the Salivary Glands

Saliva is a fluid containing water, mucin, protein, salts and enzymes. It is produced and secreted into the oral cavity by three pairs of salivary glands: the submaxillary, sublingual (or submandibular), and parotid glands (Fig. 7).

The submaxillary glands are located beneath the floor of the mouth on the inner side of the jaw. Saliva secreted from these glands enters the mouth through a duct or opening beneath the tongue known as the duct of Wharton. The sublingual glands also are located below the floor of the mouth, but closer to the mid-line and pour their saliva into the mouth through a number of small ducts—the duct of Bartholin and the duct of Rivinus. The parotid glands lie below the ears and along the sides of the jaws. The ducts from these glands enter from the inner cheek opposite the second upper molars.

The salivary glands contain both serous and mucous cells. The secretion from the serous glands is thin and watery while that from the mucous glands contains mucin and is, therefore, thicker and more slimy. These glands are controlled by the autonomic (or involuntary) nervous system and react by reflex to both direct and indirect stimulation. For example, saliva is automatically and directly produced when you take a mouthful of food, but it also can be indirectly produced when you talk about or see some food you particularly like.

Saliva has the following important functions:

• to assist in the digestion of food,

• to prepare food for swallowing by altering its consistency,

• to moisten and lubricate the mouth and lips,

• to cleanse the mouth and teeth from food debris and other foreign materials, and

• to excrete organic and inorganic substances from the body.

The latter function especially can result in serious inflammation of the oral mucosa (the lining of the mouth) and the gums.

Oral Mucosa—The Lining of the Mouth

The oral mucosa, or ''mucous membrane'' lining of the mouth, also has special functions that are important to oral health. This thin, freely movable lining is composed of several layers of epithelial cells. These are the same type of cells found on the outer layers of your skin and which serve as a protective covering. However, within the mouth, this covering lies on a thick layer of ''mucous membranes'' which secrete mucus.

As discussed earlier, mucus contains a protein material known as mucin which is formed within the cytoplasm of these epithelial cells. As the mucin accumulates,the cells become distended until they finally burst, discharging their contents onto the surface of the mouth. The mucus coats the epithelial surface serving as protection against injurious substances in the mouth or as a means to trap small foreign particles.

The production of mucus can be greatly increased by stimulation caused by infec- |

tion, allergy or temperature. We are all familiar with the increased production of mucus a caused by a cold or sore throat. Often, ''cold sores'' or ''canker sores,'' which are small 1,

•c painful ulcerations on the oral mucosa, appear during these illnesses. Therefore, the oral ^

mucosa can also be used as a mirror that reflects the general health of the body. ^

DENTAL DISEASES WORLDWIDE 2

Dental diseases including cavities (caries), tartar (calculus), sore gums (gingivitis), and s periodontitis (loss of teeth supporting the tissue) are worldwide problems. The annual cost of all dental care in the U.S. exceeds $37 billion, out of which roughly $6 billion is spent to repair the ravages of decay [1]. However, the cost of dental disease cannot simply be measured in monetary terms. Other factors also need to be considered; for example, the loss of teeth leading to impaired chewing ability, speech problems, and changes in facial aesthetics which can cause embarrassment. The well-being of a person may also be compromised due to the associated dental pain, inability to chew properly, and potential of the infection spreading from the mouth to other parts of the body [2].

Currently, a tremendous amount of time is spent by dentists and hygienists to clean the teeth and associated structures to prevent dental disease. Alternative methods to prevent dental diseases which can be used by the general population are being developed to reduce the amount of time spent with the dental professional.

Factors Affecting Delivery of Actives in the Mouth

Before discussing specific product technologies for the prevention and treatment of oral disease, we need to understand the general principles underlying the efficacy and delivery of therapeutic agents in the oral cavity (Fig. 8).

The effective use of active ingredients in oral products is depending upon several factors; some of the major ones are depicted schematically in Figure 8. Normally a therapeutic toothpaste or mouthrinse contains an active ingredient or drug which must be dissolved in the formulation. Mouthrinses currently on the market are aqueous-based formulations but contain numerous other ingredients which must be compatible with the drug. The potential for undesirable interactions between ingredients is a major concern of formu-lators and manufacturers. Some interactions are specifically designed, such as the increased solubility of poorly water soluble drugs (e.g., triclosan) by adding surfactants and other ingredients to form a microemulsion. However, incompatible ingredients are sometimes unknowingly used, especially in complex formulations where there is an incomplete understanding of the chemistry [3].

The packaging material can also be a source of compatibility problems. Any number of possible interactions can affect, either directly or indirectly, the availability of the drug in the formulation. This can usually be evaluated in the laboratory on new and aged samples of the product. Drugs which are complexed with other materials, although still soluble in the formulation, may exhibit reduced bioavailability in vivo. The term bioavailability is usually used to express a temporal relationship of free drug concentration at the target site. In this case, after mouthrinsing or toothpaste use, the bioavailability is the concentra-

P rod nets

Saliva/Oral

Packaging

Ingredients in saliva diffusion Dru9 <so1^ diffusion

Free Drug

Figure 8 Factors affecting delivery of active agents in mouth.

Elimination

tion of free drug in the environment of the target site and the rapidity at which it disappears. This can be determined providing the site can be sampled and the drug concentration measured in the medium contacting the target site (i.e., saliva, plaque fluid, crevicular fluid).

The duration of exposure may be important. Since most of the dose in the oral product is expectorated, the time in the mouth should be long enough for optimal retention of the drug. This has been determined for some orally used antiseptics such as chlorhexi-dine and triclosan. In general, 30 to 45 seconds is usually sufficient. Once introduced into the oral environment via a toothpaste/gel/mouthrinse, the residual drug must diffuse in saliva before it can reach its intended site of action. In saliva the drug is then free to interact with salivary components before reaching oral surfaces. In theory, only free available drug can interact optimally with target sites. Such sites include plaque, enamel, the gingival sulcus, gingival tissue, and the mucous membranes.

The amount of drug retained on oral surfaces after use is also thought to be important since subsequent desorption of the drug into the microenvironment of the target site could provide a sustained effect. This will be determined mainly by the substantivity of the particular drug used. Because of the long dosage interval commonly practiced with the product (once or twice a day), highly substantive drugs may have a distinct advantage because of their longer presence in the oral cavity. Superimposed upon this is the normal clearance process by which materials are removed from oral surfaces by salivary flow. The longer a drug can be retained in the environment of the target site in active form, the better chance there is to exert a therapeutic effect.

Evolution of Technologies in Oral Products

Historically, dentifrices or toothpastes were developed to keep the teeth clean and free of stains. The essential ingredients of a toothpaste are: a thickening agent, an abrasive cleaning agent, a surfactant, a humectant, flavor, and active therapeutic agents. One of the first dentifrices contained an abrasive (precipitated calcium carbonate) and a small amount of powdered soap. This toothpaste was irritating to the tissues of the mouth because the pH was relatively high due to its soap content [4]. After the Second World War, many companies undertook scientific research to develop dentifrices which were milder, gentler, and also had therapeutic properties. Instead of soap, a synthetic detergent—sodium lauryl sarcosinate—was introduced in toothpaste. Besides preventing irritation, the synthetic detergent improved the taste and was also shown to control plaque acids which cause cavities. Figure 9 provides an overview of the evolution of technologies in oral products. The category is driven by scientific advances and consumer benefits which have been broadly classified as a good smile (Fig. 9).

Stain Removal and Whitening Toothpastes

There are two types of stains on teeth: (1) stain on teeth (extrinsic stain); and (2) stain in the tooth (intrinsic stain). The extrinsic stain may originate from chromogenic materials from food or drink, while the intrinsic stain could be caused by therapeutic agents, such as tetracycline, or excessive fluoride exposure during teeth development (below age of 5). Several investigators have studied mechanisms of stain formation and developed methods to remove dental stain (Fig. 10) [5].

The evolution of whitening/cleaning technologies in toothpaste and gel is depicted in Figure 10. The most commonly used procedure for removing stains on teeth is the use

Figure 9 Evolution of technologies in oral products.

of abrasives such as silicon dioxide, dicalcium phosphate dihydrate, and aluminum salts such as calcined alumina. All these are used in combination with detergents to remove stains. In the early eighties, calcined alumina or enzymes with or without tartar control ingredient, such as pyrophosphate, were added. Later on, fluoride preparations such as hydrogen peroxide, urea peroxide, or calcium peroxides were added to remove both intrinsic and extrinsic stains. To assess performance, several laboratory tests were developed but none of them correlate with in vivo stain removal on teeth. Therefore, in vivo clinicals are the best way to assess stain removal. Typical results from in vivo studies are depicted in the table below (Table 1).

It can be seen that the addition of calcined alumina with pyrophosphate gave good stain removal in vivo. Another procedure for stain removal in vivo is by reflective spectros-

Figure 10 Evolution of cleaning/whitening technologies.

Figure 10 Evolution of cleaning/whitening technologies.

Table 1 In Vivo Stain Reduction 6 Weeks After Brushing

Dentifrice treatment

% Stain reduction

SiO2/NaF toothpaste

No change

SiO2/NaF/tripolyphosphate

14.0

SiO2/Calcined Alumina/Pyrophosphate

49.0

copy using a Minolta chromameter. The color change is measured by AE (difference in color). The higher the positive value, the whiter the teeth. Using AE in vivo, one would get AE of 2 to 4 with above technologies (in Table 1). If one adds peroxide, the value could reach as high as 6. For the reference, an in-office treatment by a dentist would provide AE of 7 to 8 following two weeks procedure.

Dentifrices to Reduce Offensive Bad Breath

Local mouth odor is caused by oral bacteria reacting with salivary proteins to form volatile sulfur compounds (VSC). Tonzetich has shown that hydrogen sulfide, methyl mercaptan, and dimethyl sulfide [H2S, CH3SH and (CH3)2S, respectively] are the major components of mouth odor. A gas chromatographic method was developed to objectively measure VSC directly from mouth air as an alternative to the organoleptic/sensory method. This instrumental method has, in turn, permitted investigators to carry out studies in a number of areas relevant to human malodor [6]. There are two methods currently available to assess the magnitude of oral malodor. The first is the organoleptic or sensory rating approach, and the second is the GC instrumental method. A study was conducted to determine the correlation between these two methods in a controlled clinical study. An excellent correlation (r = 0.78) has been established between the instrumental method and sensory evaluation. Using the analytical technique, the effect of dentifrices on mouth odor has been evaluated in a variety of clinicals. A baseline reading is taken in the morning. The subjects then brushed with a placebo or an active dentifrice, and then readings are taken three or 12 hours post-treatment to assess the effects. A dentifrice containing the antibacterial triclosan and a copolymer polyvinyl methyl ether maleic acid (PVM/MA) has been developed. This provides sustained reduction in mouth odor. The typical clinical results are summarized in Figure 11 [7].

Therapeutic Dentifrices

Dentifrices to Control Caries (Cavity)

It is well-known that the formation of dental caries is a result of interactions between the tooth enamel, environment (saliva), plaque fluid and ingestion of dietary carbohydrates. These interactions are also important in the formation of dental plaque on teeth. Dental plaque plays an important role in the formation of caries since it is the plaque bacteria which produce acids from sugars. However, the production of acids by plaque bacteria and subsequent dissolution of tooth enamel is not a constant process. Instead, it appears to be cyclical. At a given time, plaque acids attack the enamel surface and deplete it of minerals, creating a small microtrauma at the surface. These areas are actually called incipient caries or white spots and occur long before caries can be detected by dentists or hygienists. If left unchecked, the process eventually results in destruction of the teeth.

Figure H Plot of breath odor scores

Figure H Plot of breath odor scores

Since caries is not a continuous process, early lesions can be repaired through interactions of various elements in the oral environment, that is, supersaturation with respect to calcium phosphate in saliva, fluoride and pH of the plaque fluid [8].

Tooth enamel is not a smooth impervious surface, instead it is porous, and an apparent lack of activity on the surface may mask actual activity below. In order to create a caries lesion, the acids must penetrate the enamel structure, which consists of hydroxyapa-tite (HA) crystals surrounded by an organic matrix consisting of water, protein and lipid materials and this they do by removing some of the mineral from the crystalline rods below the surface of the teeth. This demineralization weakens the structure and, if unchecked, eventually results in a subsurface lesion often called a white spot which will appear to be chalky and whiter than the normal surrounding tooth surface. Continuation of the de-mineralization process results in the creation of cavities. This occurs when the surface enamel collapses as the underlying structure of mineral rods can no longer maintain the tooth structure. However, not all white spot lesions progress to cavities, and one of the prime reasons being the process of remineralization which occurs when minerals are rede-posited into the enamel that has been weakened by bacterial acids. Remineralization can, therefore, only take place when there has been loss of tooth structure through demineraliza-tion. Thus, demineralization and remineralization are continuous processes with loss from, and replacement of, minerals into enamel within the oral environment. The most soluble mineral in the teeth is thereby replaced by the most insoluble calcium phosphate, such as dicalcium phosphate dihydrate (DCPD). If the environment is rich in DCPD, the process of remineralization occurs. This process is greatly enhanced by fluoride ions which convert DCPD into fluorohydroxyapatite which forms onto, and within, the tooth increasing resistance to acid attack [9].

Fluoride increases remineralization by increasing the rate of crystal growth, but to restore tooth structure a supersaturation of calcium phosphate in the environment is also necessary. The process of remineralization has been shown to be controlled by the presence of fluoride and a supersaturation of calcium and phosphate in plaque fluid. Thus, the tooth and environment are in a seesaw battle. Under healthy conditions when supersaturation is high and plaque acids are low, the ambient calcium phosphate (DCPD) in plaque fluid

Figure 12 Average percent mineral changes for enamel and dentin.

NaF NaF/PP Placebo Treatment

Figure 12 Average percent mineral changes for enamel and dentin.

is sufficient to maintain healthy enamel. When the caries challenge is high and plaque is producing more acids, supersaturation with respect to DCPD decreases and demineraliza-tion occurs. Fluoride inhibits lesion formation by enhancing the process of remineraliza-tion, and this enhancement is greatly influenced by supersaturation of the plaque fluid with respect to HA.

Fluoride dentifrices are capable of adding minerals (remineralization) to early caries lesions. This process can be measured in vivo by using the model of intra-oral remineral-ization. A dose response effect of fluoride is shown in Figure 12 which shows the percent mineral gains in either enamel or dentine following two weeks use of either 1100 ppm F from MFP (sodium monofluorophosphate) or sodium fluoride, NaF. Both fluoridating systems extend the same degree of mineralization as an equal concentration. Human clinical studies for caries (cavity) prevention require 3 years to document anti-caries effect. In those studies, mean reduction in caries varies from 25 to 40% depending upon the population used in the study and whether or not the study area had water fluoridation. Current efforts are to enhance efficacy of 1000 to 1500 ppm of fluoride in dentifrices with additives such as xylitol, a non-fermentable sugar, or the antibacterial triclosan. These additives have been shown to boost the effectiveness of fluoride in toothpaste (Figs. 12, 13) [10].

Figure 14 Data from ''Oral Health of U.S. Adults," NIDR, 1985.

Anticalculus and Anticavity Technologies

Calculus build-up on teeth is a worldwide problem. For nearly 5,000 years since the time of the Sumerians, calculus has been considered an important factor in the etiology of periodontal diseases. Although it is not considered to be a principle cause of periodontal diseases today, calculus is an important contributor to the formation of dental plaque which is implicated in periodontal disease. At a given time, hundreds—even thousands—of hy-gienists around the world are removing calculus build-up by mechanical cleaning. These procedures are very labor-intensive and may cause a great deal of discomfort to the patient.

The extent and incidence of calculus in the general U.S. population has been shown in a comprehensive oral health survey by the National Institute of Dental Research [11]. The data shown in Figures 14 and 15 indicate the incidence of calculus. Calculus was observed in 34% of school-aged children. In adults, 25 to 30% had calculus build-up above the gingival margin, but 60-65% had deposit below the gingival margin. Older adults showed an even higher incidence. The extent of calculus in the population indicates a need to develop an effective but safe chemical means to prevent calculus build-up on the teeth. This is especially important for the countries where the dentists and hygienists are not readily available (21). Therefore, the development of the technologies to prevent calculus is important around the world from a public health point of view (Figs. 14, 15).

Chemical Composition of Dental Calculi on Teeth and Dental Materials

Dental calculus consists of both organic and inorganic components. The organic portion is a combination of epithelial cells, leukocytes, micro-organisms, and polysaccharides.

Figure 15 Calculus in U.S. population (seniors, ''Oral Health of U.S. Adults," NIDR, 1985).

Figure 15 Calculus in U.S. population (seniors, ''Oral Health of U.S. Adults," NIDR, 1985).

The inorganic part is primarily calcium phosphate salts which include: carbonated hy-droxyapatite (CHA), dicalcium phosphate dihydrate (DCPD), and octacalcium phosphate (OCP). The x-ray diffraction patterns and infrared absorption spectra of human dental calculi and the samples obtained from the dentures and tooth surfaces show that the inorganic component of calculus from dentures is principally carbonated hydroxyapatite (CHA), while material from tooth surfaces is a mixed calcium phosphate phase P-TCPC Mg-substituted), CHA, and OCP. The deposits then are primarily basic calcium and phosphate salts [12].

Technologies for the Prevention of Calculus Formation

A general method of removing calculus is by mechanical means. The mechanical means are labor-intensive and painful. Another approach is to develop a chemical way of preventing the formation of the basic phases of calcium phosphates. A large number of agents have been proposed to retard the formation of calculus on to surfaces. These agents are usually compounds which inhibit the formation of calcium phosphate salts to the crystalline phases. Among the most effective inhibitors are pyrophosphate, pyrophosphate plus polymer and zinc salts. In general, agents usually work via a surface effect. The inhibitors adsorb to the growing (calcium phosphate) crystals and they reduce the formation of crystalline phases allowing calcium phosphate to remain in an amorphous phase. In general, two types of tests have been used to evaluate the inhibitors. One test follows the spontaneous formation of HA (Fig. 16) using a supersaturation environment which stimulates the plaque fluid. The second test is a seeded crystal growth for hydroxyapatite which uses the driving force equivalent to saliva environment (Fig. 17). Using these tests, the relative value of efficacy of these inhibitors is summarized, shown in Table 2. It shows that the most active inhibitor is pyrophosphate. Also a combination of pyrophosphate and the copolymer of pyrophosphate and the copolymer (PVM/MA) provides an enhanced efficacy. Zinc salts, on the other hand, require a higher concentration for effectiveness. The relative clinical efficacy of these agents in various dentifrices are summarized in Table 3. Available data from the composite of several clinical studies indicate that calculus inhibition with the pyrophosphate and sodium fluoride combination is roughly in the range of 26%; with the copolymer/pyrophosphate (1.3% soluble pyrophosphate to 3.3%) the

Figure 16 HAP formation.

5Ca2+ + 3HPO42- + H2O ^ Ca5(PO4)3OH + 4H+ Figure 17 Crystal growth.

calculus reduction ranged as high as 50%; zinc salts require higher concentration for efficacy (2% or above). With a lower concentration (0.5%), the efficacy against supergingival calculus formation is very poor [13].

Mechanisms of Action of Anticalculus Agents

The mechanism for the inhibition of calculus formation by anticalculus agents are schematically illustrated. The calcium and phosphate from saliva or from plaque fluid precipitate and form a precrystalline phase which matures to crystal phase in the absence of inhibitor. In the presence of inhibitor that amorphous phase is stabilized and the conversion of the crystalline phase is delayed. This is clearly evident from the electronmicrographs of calculus formed in the presence and the absence of inhibitor. In the absence of inhibitor, the crystal size was very large and well-defined; in the presence of an inhibitor, the deposit was very small and has morphology of amorphous calcium phosphate (Fig. 18).

The current technologies used for inhibiting calculus formation also contains fluoride. When the application of a potent inhibitor of calcium and phosphate crystal growth coexists with fluoride, a crystal growth promoter, we need to understand how they work together. The inhibitor prevents the formation of HA. Then how do two agents coexist in the same system and exert the respective effect? Our early data indicated that crystal growth inhibitors work on tooth surfaces while fluoride ion works within teeth. The effect can be explained by the fact that the calculus formation occurs on the teeth (above) where the demineralization occurs in the subsurface region of the enamel (under pellicle). The presence of pellicle on the tooth allows the selective transport of fluoride and the inhibitor. This mechanism has been elucidated by studies of natural inhibitors of crystal growth in

Table 2 Calculus-Control Technologies: Relative Efficacy

Inhibition

Compound

(ppm)

Pyrophosphate

4.0

Pyrophosphate + copolymer

3.0

Zinc

60.0

Table 3 Clinical Efficacy of Toothpastes in Humans

Mean reduction in

Toothpaste calculus vs. placebo

3.3% pyrophosphate + NaF 26%

2% zinc + sodium fluoride 38-50%

Abbreviation: PVM/MA, copolymer polyvinymethyl maleic acid. Source: Ref. 13.

saliva. The study indicated that the crystal growth inhibitory effect of the natural inhibitor can be overcome by the addition of fluoride. This effect was neither due to displacement of an adsorbed inhibitor by fluoride nor the activation of secondary growth sides. Rather the effect was explained on the basis of increased driving force of precipitation and incomplete blockage of crystal growth sites on the basis of steric effect. This has now been confirmed via in vivo studies.

Technologies to Reduce Tooth Sensitivity

The next evolution of toothpaste chemistry was developed as a means to prevent pain caused by sensitive teeth; i.e., hypersensitivity. Dentinal hypersensitivity is defined as an acute, localized tooth pain in response to thermal, tactile, or air blast stimulation to exposed dentine surfaces. Normally, the roots of teeth are covered by the gingival or gum tissue but when the gum recedes, the underlying tooth surface is exposed. Once exposed, with time, abrasion and erosion will remove the thin layer of cementum, thus exposing underlying porous dentine. Exposure of the dentine surface to dietary or bacterial acids can expose

Precalculus

Figure IS Mechanism of pyrophosphate/copolymer/NaF on tartar formation.

Precalculus

Figure IS Mechanism of pyrophosphate/copolymer/NaF on tartar formation.

Figure 19 (a) Open dentinal tubules. (b) Occluded dentinal tubules.

the dentine pores or tubules at the surface. It is well known that exposure and the presence of open tubules (Fig. 19a) on the surface is associated with increased dentinal hypersensitivity. The dentine tubes contain fluid.

Mechanistically, hot or cold stimuli can cause this fluid to expand or shrink, stimulating underlying pulpal nerve resulting in pain. Currently, salts of potassium are available as preventive therapies in OTC toothpaste. Various other agents such as potassium nitrate are believed to cause reduction in nerve activity by altering the threshold of pulpal nerve excitation. These approaches have been combined in a single toothpaste containing potassium nitrate and copolymer which adhere to tooth surfaces. Figure 19b shows occlusion

Figure 20 Microbiota (health vs. disease).

which can result from in vitro treatment of dentine with such a toothpaste. Unfortunately, this therapy requires two to three weeks treatment before a reduction in sensitivity is observed. Therefore, there is currently a strong need for a fast reactive material in toothpaste which could rapidly reduce dentinal hypersensitivity (Figs. 19a,b) [14].

Multibenefit Technologies in Dentifrices

The next development in dentifrice technology was to incorporate antibacterial agents with fluoride and tartar reducing compounds.

Microbiota of Dental Plaque: Health Versus Disease

The basic research within the past 30 years clearly established the role of dental plaque at the interfaces of tooth/gingiva as the main cause of gingival inflammation, which could lead eventually to periodontitis. The previous studies by Loe et al. [15] and subsequent studies by Syed [16] and Loesche indicated that there was threshold level of bacteria which was compatible with gingival health. When that threshold level of bacteria increased by at least two or three orders of magnitude, then gingival inflammation was initiated. Therefore, the prime purpose of chemical antiplaque agents is to bring the microflora to a healthy level at the gingival interfaces, primarily by reducing the total mass of microbiota at the surface, or by reducing the total number of pathogens at the surface (Figs. 20, 21).

Since dental plaque is principally composed of microorganisms, it is logical to use antibacterials to reduce or prevent plaque formation. The rationale is that the antibacterials will either inactivate bacteria in the existing plaque or prevent colonization. However, early studies clearly showed that 99% of bacteria in the oral cavity must be killed in order to inhibit plaque formation for only 6 hours, provided teeth are brushed twice daily. Since

Figure 21 Therapeutic strategies.

Figure 21 Therapeutic strategies.

Table 4 Characteristics of Antibacterials for Plaque Effects

Broad spectrum antibacterial activity Substantivity to oral surfaces Good taste

Compatible with toothpaste ingredients Low toxicity

No disturbance of oral ecology the oral cavity is an open system, the chance of continued reinfection is ever present. Based on recent studies, the general characteristics of antibacterial agents useful for an antiplaque effect can be summarized in Table 4. For an antibacterial antiplaque agent to be effective, a broad-spectrum activity against oral microflora is required, since the microbial composition of the plaque is complex. With cationic antibacterial agents, a minimum inhibitory concentration in the range of 0.1 to 0.5 |g/ml against oral pathogens has been noted. However, the current understanding of the pharmacology of antibacterial antiplaque agents indicates that there are factors other than antibacterial activity in determining sustained antiplaque effect on teeth. These factors include the retention and release of antibacterials on oral surfaces, as well as their efficacy in the presence of the salivary environment. Furthermore, it is important that a given antibacterial does not disturb taste, otherwise the patient's compliance would be very poor. Another consideration for use in oral products is compatibility with polishing agents and surfactants, since both of these ingredients are important for controlling stain on teeth, as well as emulsifying flavor oils, which are incorporated in the oral hygiene products for compliance. Other important considerations are a low toxicity and a minimum potential to disturb the normal microbial oral ecology [17].

Cationic Antibacterial Agents

Among the widely studied agents are cationic antibacterials such as chlorhexidine digluco-nate (CHDG), benzethonium chloride (BTC), and cetyl pyridium chloride (CPC). CHDG is more effective than BTC or CPC and has higher retention in the oral environment. They also differ with respect to their reaction with salivary protein, which is an important parameter for the retention of cationic antibacterials on oral surfaces; increased retention provides a sustained release of concentrations active against oral pathogens.

Long-term clinical studies have demonstrated the efficacy of cationic antibacterials against plaque, gingivitis and plaque microflora. However, these agents cause unacceptable staining of teeth and an increase in calculus formation. Therefore, their use in oral hygiene products clearly is limited [17].

Noncationic Antibacterial Agents

More recently (during the past 10 years), there has been tremendous interest in non-cat-ionic antibacterials which provide multi-benefits such as plaque, gingivitis, calculus, and caries reduction. This is primarily based on a non-ionic antibacterial agent, triclosan, which has broad-spectrum antibacterial activity against gram-positive and gram-negative bacteria. For triclosan to be effective, a delivery system is required to increase its residence time in the oral cavity. A copolymer of polyvinyl methyl ether (PVM) and maleic acid (MA) has been shown to accomplish that. This copolymer was well-suited for improving the delivery of triclosan, since PVM/MA has been shown to react with hard and soft

Table 5 Noncationic Antibacterials: Comparative Study for In Vivo Plaque Inhibition

Treatment

Mean P surfaces

on all ± SD

SNK group

Placebo

1.46 ±

0.12

A

0.12% CHDG

0.53 ±

0.17

B

0.2% SnF2 (rinse)

1.10 ±

0.16

C

0.06 Triclosan

1.00 ±

0.14

C

0.06 Triclosan + Gantrez

0.72 ±

0.17

B

0.06 Triclosan + PVPA

0.67 ±

0.16

B

Abbreviations: Gantrez, PVM/MA, polyvinyl methyl/maleic acid; PVPA, polyvinylphosphonic acid; SNK, Student Neuman Keuls test; P, plaque index.

Abbreviations: Gantrez, PVM/MA, polyvinyl methyl/maleic acid; PVPA, polyvinylphosphonic acid; SNK, Student Neuman Keuls test; P, plaque index.

surfaces in the oral cavity. In a four-day short-term study of de novo plaque formation, we evaluated a series of different antibacterial agents. We found that triclosan actually needs an improved delivery system, primarily a copolymer, to enhance its retention to both tooth and oral epithelial surfaces [18].

One of the important principles developed is that retention per se is not the only factor in antiplaque activity; the retained concentration has to be active biologically. To demonstrate this principle, we conducted a series of studies to understand how much triclosan was retained post-brushing. In one of the studies, we compared three triclosan formulations, each having a different enhancing system (Table 5). As can be seen in Table 6, even after 14 hours, a significant amount is retained in plaque, a concentration above the MIC's of triclosan for oral bacteria (MIC being 0.3-4 |g/mL). The next important step was to determine whether this retained amount was active biologically. A plaque viability assay was used, in which we exposed the plaque to two fluorescent dyes to discriminate between live and dead bacteria by measuring the ratio of green to red fluorescence. In this study, one could quantitatively measure the ratio and ascertain whether the retained amount was active biologically. In one of the typical studies shown here, brushing with the placebo toothpaste gave some reduction of plaque viability; the triclosan copoly-mer system gave the highest reduction in viability, and the other systems, such as triclosan/ pyrophosphate and triclosan/zinc citrate, were not significantly different from the placebo (Fig. 22). These results have been corroborated by an independent six-month clinical study by Renvert and Birkhed (Table 6) [19].

The mechanism by which the copolymer enhances the delivery of triclosan has been elucidated (Fig. 23). The polymer has two groups: one is the attachment group and the other is the solubilizing group. The solubilizing group retains triclosan in surfactant mi-

Table 6 Plaque Triclosan Levels After Brushing (|g/mL)

0.3% Triclosan/

0.3% Triclosan/

0.3% Triclosan/

After

copolymer

pyrophosphate

1% zinc

brushing

n = 12

n = 12

n = 12

2 h

38.83 ± 18.28*

20.90 ± 14.14

30.60 ± 13.6

14 h

4.14 ± 1.72

2.74 ± 2.11

3.95 ± 1.79

: P = 0.05, compared with a placebo toothpaste.

: P = 0.05, compared with a placebo toothpaste.

Figure 22 Plaque viability study determined via a fluorescent-dye technique.
Figure 23 Mechanism of retention of triclosan on oral surfaces by the copolymer. The solubi-lizing group (methoxyether) traps triclosan/surfactant micelle while the attachment group (COOH) binds to calcium in an adherent liquid layer on tooth /enamel interface.

Table 7 Therapeutic Mouthrinses

Typical reduction in the diseases

Mouthrinse Active agents vs. placebo

Fluoride rinses 225 ppm F 50% reduction in caries, children

Tartar + calculus 1% pyrophosphate amion; 100 30-35% reduction in tartar forma-

ppm F plus a copolymer of tion after 6 months use PVM/MA (0.5%)

Antiplaque/antigingivitis 0.03 to 0.06 Triclosan + 1% 20-30% reduction in plaque/gingi-

copolymer PVM/MA + vitis after 3 months of use fluoride celles, and the attachment group reacts with the oral surfaces via calcium in the liquid adherent layer. Triclosan is then slowly released via interactions with salivary environment. In terms of long-term clinical trials, this technology has now been evaluated around the world in 12 six-month plaque/gingivitis studies, three calculus studies, three caries clinical trials, and five long-term studies monitoring the oral microbial population. The results of all these studies indicated that this technology was effective against plaque, gingivitis, calculus, and caries. No side effects of staining or calculus increase were seen. There was also no disturbance of the oral microbial ecology.

One of the most exciting aspects of triclosan is its ''double-barrel'' effect. This unique antibacterial not only kills bacteria, but also neutralizes the products of bacteria which could provoke inflammation. We have shown that triclosan was a potent inhibitor of both cyclo-oxygenase and lipoxygenase pathways. It not only inhibited these enzymes in vitro but also inhibited the release of their products (prostaglandins and leukotrienes) in gingival fibroblasts which were stimulated by interleukin 1-0. These data were clinically confirmed in a study in which we blocked the antibacterial effect of triclosan but maintained its anti-inflammatory effect. Thus, triclosan has a ''double barrel'' effect—both antibacterial and anti-inflammatory. This unique feature is not provided so far by other antibacterial, anti-plaque agents [20].

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