Journal of Dental Research http://jdr.sagepub.com/
Delivery of Antiplaque Agents from Dentifrices, Gels, and Mouthwashes D. Cummins and J.E. Creeth J DENT RES 1992 71: 1439 DOI: 10.1177/00220345920710071601 The online version of this article can be found at: http://jdr.sagepub.com/content/71/7/1439
Published by: http://www.sagepublications.com
On behalf of: International and American Associations for Dental Research
Additional services and information for Journal of Dental Research can be found at: Email Alerts: http://jdr.sagepub.com/cgi/alerts Subscriptions: http://jdr.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jdr.sagepub.com/content/71/7/1439.refs.html
>> Version of Record - Jul 1, 1992 What is This?
Downloaded from jdr.sagepub.com at Universitats-Landesbibliothek on November 3, 2013 For personal use only. No other uses without permission.
Delivery of Antiplaque Agents from Dentifrices, Gels, and Mouthwashes D. CUMMINS and J.E. CREETH Unilever Dental Research, Port Sunlight Laboratory, Quarry Road East, Bebington, Wirral L63 3JW, England Antiplaque agents delivered from toothpastes, gels, or mouthrinses can augment mechanical oral hygiene procedures to control the formation of supragingival plaque and the development of early periodontal disease. Clinically effective antiplaque agents are characterized by a combination of intrinsic antibacterial activity and good oral retention properties. The overall oral retention of an antiplaque agent is determined by the strength and rate of association of the agent with its receptor sites and the accessibility of these sites. The substantivity of an antiplaque agent and its clearance from the oral cavity are determined by the rate of dissociation of the agent from the receptor sites and the salivary composition and flow rate. Positively charged and non-charged organic molecules, metal ions, enzymes, and surface-active agents have all been considered as antiplaque agents. To exert clinical antiplaque activity, an antimicrobial agent must be formulated in a chemically compatible delivery vehicle to give optimal release and uptake to the sites of action in a biologically active form during its time of application. In principle, antiplaque activity may be enhanced by combining antimicrobial agents with broadly similar, but complementary, modes of action. Alternatively, the activity of a single agent may be increased by use of a retention aid to enhance oral substantivity. Substantial evidence exists to demonstrate the validity of the first approach. However, there are few data, as yet, to support the effectiveness of the second. The oral mucosa is the bulk retention site for all clinically proven antiplaque agents. Plaque, the pellicle-coated tooth surface, and saliva are probably all sites of biological action. A detailed understanding of the interactions between agents and the various receptor sites, and of the importance ofthese receptor sites to biological activity, is generally lacking.
principles governing the oral delivery and clearance of antiplaque agents and the properties of dentifrices relating to their role as delivery vehicles; (iii) to review oral substantivity and clinical data for specific antiplaque agents; and (iv) to identify generic routes to enhance antiplaque efficacy and to review evidence for their effectiveness in vivo. Thus, it is intended to provide a view ofthe current state of knowledge and understanding of the delivery, substantivity, and mechanisms of retention of antiplaque agents from dentifrices, gels, and mouthrinses and the importance of these considerations to efficacy.
The key biological properties of antiplaque agents.
An antiplaque agent for use as a routine aid to mechanical oral hygiene procedures should possess the following properties: inherent biological activity consistent with its specific mode of antiplaque action, good oral substantivity, low toxicity, and low permeability. Each has a role in determining the dose, frequency of use, and delivery route of the agent. Antiplaque activity may be achieved in various ways. These include reducing the adhesion of bacteria to the tooth surface, inhibiting the growth and proliferation of micro-organisms on the tooth surface, inhibiting the formation of the intercellular plaque matrix, modifying plaque biochemistry to reduce the formation of cytotoxic products, and modifying plaque ecology to a less pathogenic flora (Cummins, 1991a). To function effectively as an antiplaque agent in vivo, an agent must be delivered to its site or sites of action in a biologically active form during the time of application, and it must be retained there for a sufficient period to exert its biological effect (Gjermo et al., 1970; Goodson, 1989; Van der Ouderaa and Cummins, 1989). The most successful antiplaque approach, to date, has been J Dent Res 71(7):1439-1449, July, 1992 the use of broad-spectrum antimicrobial agents such as chlorhexidine, metal ions, and phenolic compounds, which are subIntroduction. stantive to oral surfaces (Cummins, 1992). The efficacy of such agents is generally believed to result from the slow release of Supragingival plaque formation and the onset of early periodontal bound agent from these oral surfaces to give a level in saliva disease can be successfully controlled by scrupulous mechanical capable of inhibiting bacterial growth and, hence, plaque accuoral hygiene procedures (Lindhe and Nyman, 1975; Axelsson and mulation for an extended period between applications. A typical Lindhe, 1978;Abdellatif and Burt, 1987;Attstr6m, 1988). However, substantivity profile is illustrated in Fig. 1. In contrast, agents the dedication and motivation required to achieve such control is not which are antibacterial but which are not substantive are able the norm for most individuals. A typical response to prophylaxis, to act for only a relatively short time period after application, brushing instruction, and motivation is a temporary improvement with the result that the bacterial population is able to recover in gingival health which is lost in the absence of further motivation rapidly to normal levels, and plaque growth is unaffected. A (Svatunetal., 1990; Stephenetal., 1990). There is, therefore, a clear profile typical of a non-substantive agent is also illustrated in rationale for the use of antiplaque agents to augment mechanical Fig. 1. oral hygiene procedures (Kornman, 1986; Newman, 1986; Mandel, Although this representation is useful (see, for example, 1988; Van der Ouderaa, 1991). Goodson, 1989), a number of additional considerations should be In principle, a dentifrice provides an excellent vehicle for the borne in mind. First, this mechanism ignores the role of antidelivery of antiplaque agents because, in many societies, the ha- plaque agent bound to tooth surfaces in preventing plaque growth bitual use of a dentifrice is part ofnormal daily hygiene. In practice, on these surfaces and that bound to the plaque itself. Second, however, few agents have been successfully formulated to give the minimum inhibitory concentration (MIC) of an agent in the clinically active products (Kornman, 1986; Van der Ouderaa, 1992). mouth may be quite different from that normally measured in The aims of this paper are: (i) to summarize briefly the key vitro in broth culture. Clear differences in MIC's have been biological properties of antiplaque agents; (ii) to discuss the demonstrated for agents measured in broth culture and in saliva in vitro (Roberts and Addy, 1981), presumably due to differing Presented at the symposium on "New Agents in the Chemical Control of interactions with proteins (Hjeljord et al., 1973). Finally, growth Plaque and Gingivitis", during the IADR's 69th General Session, April 17, of bacteria may be retarded at concentrations well below the MIC (at which growth is stopped) of any given agent (Marsh, 1991). 1991, Acapulco, Mexico 1439
J Dent Res July 1992
CUMMINS & CREETH
1440
TABLE la SUMMARY OF PUBLISHED ORAL SUBSTANTIVITY DATA FOR CATIONIC ANTIMICROBIAL COMPOUNDS
Agent (vehicle) Chlorhexidine (mouthwash)
Total retention (%) 32 (pH 6.4)
Chlorhexidine (Gel)
32
References Bonesvoll et al., 1974a Bonesvoll and Gjermo, 1978 Bonesvoll et al., 1974a Bonesvoll, 1977a
Cetylpyridinium chloride (mouthwash)
65
Bonesvoll and Gjermo, 1978
Hexadecyl trimethyl ammonium bromide (mouthwash)
70
Bonesvoll and Gjermo, 1978
Sanguinarine (mouthwash) ND = Not determined. n= number of participants.
ND
Southard et al., 1984
12 (pH 3)
Thus, it is difficult to estimate a meaningful concentration above which antimicrobial activity of an agent is manifest in vivo (cf Goodson, 1989). Even though the relative activities ofthese substantive, broadspectrum, antimicrobial agents vary widely, they all appear to act multifunctionally to reduce bacterial adhesion, growth, and metabolism and, hence, to reduce plaque mass and plaque pathogenicity (Cummins, 1992). The oral mucosa has a low permeability barrier and is, therefore, an efficient tissue for the absorption of topically applied agents. As a result, antiplaque agents which are intended for topical delivery must have low acute and chronic toxicity and, preferably, low permeability (Goodson, 1989). Most of the topically applied antiplaque agents which are currently in use-such as chlorhexidine, quaternary ammonium compounds (Goodson, 1989), metal ions, and Triclosan (De Salva et al., 1989)-satisfy these criteria.
Ginneken, 1977). Hence, the retention of an agent is concentration-driven. The initial retention and distribution of an antiplaque agent within the oral cavity are determined by the strength (K1, etc.) and the rate of formation (kal, etc.) ofthe interactions between the agent and its various receptor sites (Fig. 3) and their accessibility. Current antiplaque agents appear to adhere to all surfaces within the mouth: the tooth pellicle, the oral epithelia (including the buccal mucosa, gingival tissues, and tongue), and supragingival plaque. Depending upon the specific mode of action of the antiplaque agent, these various receptor sites will be either sites of biological action or reservoirs (Goodson, 1989), as illustrated in Fig. 4. Saliva compositionwill influence oral speciation ifthe antiplaque agent binds to salivary protein, glycoprotein, or lipid via any of the interaction forces mentioned above. Clearance of an antiplaque agent from the mouth is controlled by the strength of binding (K1, etc.) and the rate of release (kbs, etc.) Principles of the delivery and clearance from the receptor sites (Goodson, 1989; Van der Ouderaa and of antiplaque agents in the mouth. Cummins, 1989). Saliva composition and salivary flow rate are key There are two sequential phases governing the oral retention of influences on these two factors. The kinetics of the clearance of nonan antiplaque agent: the release of the agent from the delivery binding substances from the mouth has been mathematically modvehicle and subsequent uptake of the agent to receptor sites. eled (Dawes, 1983) and subsequently extended to the clearance of Saliva may mediate between the delivery vehicle and the receptor substantive agents byuse ofsingle-reservoir (Gilbert, 1987; Goodson, sites, or the uptake may be direct, as depicted in Fig. 2. 1989) and double-reservoir (Wagner, 1975; Gilbert and Williams, The "release" phase is dependent on the diffusion coefficient 1987) models. It has been clearly demonstrated that individuals of the antiplaque agent from the vehicle during application. The vary substantially in the potential benefit they may attain from "uptake" to the receptor sites involves well-characterized physi- rinsing with an antiplaque agent, as a result of differences in their cochemical interactions, i.e., electrostatic, hydrophobic, and li- salivary flow rates (Goodson, 1989). Furthermore, elevated levels pophilic interactions, hydrogen bonding, and Van der Waals' of an antiplaque agent have been predicted to follow a night-time forces. Both phases are governed by first-order kinetics (Van rinse, due to low salivary flow rates during sleep (Goodson, 1989). Conc. of agent in saliva t\= < ~~Substantive
RELEASE PHASE
CLEARANCE PHASE
ISALIVA
DELIVERY VEHICLE
LOSS
(to or
\
IMinimum inhibitory
Non-substantive
I,/ agent
\
CLEARANCE PHASE
UPTAKE PHASE
concentration
Time-+ 1st dose
swallowing
expectoration)
2nd dose
Fig. 1-Hypothetical clearance curves for substantive and non-substantive agents from the oral surfaces.
ORAL RECEPTOR
SITES
Fig. 2-Model of the delivery and clearance of an antiplaque agent in the mouth.
Vol. 71 No. 7
DELIVERY OFANTIPLAQUE AGENTS
1441
TABLE lb PHARMACOKINETIC DATA CALCULATED FROM PUBLISHED DATA FOR CATIONIC ANTIMICROBIAL COMPOUNDS Dose Agent (vehicle)
(Ag)
Chlorhexidine (mouthwash) 20,000 7870 Cetylpyridinium chloride(mouthwash) Hexadecyl trimethyl ammonium 8010 bromide (mouthwash) Sanguinarine (mouthwash) 6740 x 2 = ND Not determined.
Total retention (%) 32
AO
kel
(iglg) 224
(min-') 0.0155
65
107
70
ND
Salivary flow rate has also been demonstrated to affect clearance of an unbound agent differentially according to its location within the mouth (LeComte and Dawes, 1987). It is likely, therefore, that clearance of a substantive antiplaque agent-whether from plaque, tooth pellicle, or oral mucosa-will be most rapid close to salivary ducts and slowest in the more stagnant areas of the mouth. This concept may have important implications for pharmacokinetic and clinical studies of antiplaque agents, but as yet it appears to have been largely ignored by researchers in these fields. The portion of the antiplaque agent which is retained in the oral cavity after application and which is available at the site or sites of action may be defined as the "bioactive" portion. This bioactive portion is by no means the total amount of the agent present, because the agent may be retained in irrelevant oral reservoirs which have no role in activity. It is the effect ofthis bioactive portion which, integrated over time, gives rise to clinical activity and, thus, should be maximized (Van der Ouderaa and Cummins, 1989). If there is no adsorption or binding of an agent within the oral cavity, then the agent must possess sufficient biological activity to be clinically effective within the short time [< 15 min (Dawes, 1983)] that it is present in the mouth. In practice, there are few examples of agents in this category.
General factors governing the delivery of an antiplaque agent to and its clearance from the oral cavity. Solubility.-Classically, an antiplaque agent must be solubilized in its delivery vehicle so that rapid release into the oral environment occurs, particularly when the application time is short. The digluconate salt of chlorhexidine, for instance, was selected for the development of chlorhexidine mouthrinses due to its high aqueous solubility (Senior, 1972). Similarly, Triclosan (2,4,4'-trichloro-2 hydroxydiphenyl ether), which has poor aqueous solubility, is solubilized in the flavor/surfactant phase of a dentifrice (Lane et al., 1985) which facilitates its release and retention during application (Gilbert, 1987; Gilbert and Williams, 1987). The solubility ofan agent does not solely determine its bioactivity, however. Stabilizing an agent in solution may diminish its tendency to adsorb onto the oral surfaces, because its chemical potential is reduced. This may occur for metal ions, for example, by complexation with ligands (Cummins and Watson, 1989). Similarly, this may occur for sparingly soluble organic species by interaction with the surfactant or flavor oils (Lane et al., 1985). The balance between solubility and stability in solution, on the one hand, and bioavailability, on the other, is very important to the degree of clinical benefit achievable. An alternative approach to effect delivery is to deposit an antiplaque agent in the form of sparingly soluble particles within the oral cavity such that they deliver low doses of the agent over a
0.0186
AUC [ig (%)] 7226 (36) 2876(36)
Bonesvoll and Gjermo, 1978 Bonesvoll and Gjermo, 1978
158
0.0226
3496 (44)
Bonesvoll and Gjermo, 1978
1.48
0.014
53 (
Delivery of Antiplaque Agents from Dentifrices, Gels, and Mouthwashes D. Cummins and J.E. Creeth J DENT RES 1992 71: 1439 DOI: 10.1177/00220345920710071601 The online version of this article can be found at: http://jdr.sagepub.com/content/71/7/1439
Published by: http://www.sagepublications.com
On behalf of: International and American Associations for Dental Research
Additional services and information for Journal of Dental Research can be found at: Email Alerts: http://jdr.sagepub.com/cgi/alerts Subscriptions: http://jdr.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jdr.sagepub.com/content/71/7/1439.refs.html
>> Version of Record - Jul 1, 1992 What is This?
Downloaded from jdr.sagepub.com at Universitats-Landesbibliothek on November 3, 2013 For personal use only. No other uses without permission.
Delivery of Antiplaque Agents from Dentifrices, Gels, and Mouthwashes D. CUMMINS and J.E. CREETH Unilever Dental Research, Port Sunlight Laboratory, Quarry Road East, Bebington, Wirral L63 3JW, England Antiplaque agents delivered from toothpastes, gels, or mouthrinses can augment mechanical oral hygiene procedures to control the formation of supragingival plaque and the development of early periodontal disease. Clinically effective antiplaque agents are characterized by a combination of intrinsic antibacterial activity and good oral retention properties. The overall oral retention of an antiplaque agent is determined by the strength and rate of association of the agent with its receptor sites and the accessibility of these sites. The substantivity of an antiplaque agent and its clearance from the oral cavity are determined by the rate of dissociation of the agent from the receptor sites and the salivary composition and flow rate. Positively charged and non-charged organic molecules, metal ions, enzymes, and surface-active agents have all been considered as antiplaque agents. To exert clinical antiplaque activity, an antimicrobial agent must be formulated in a chemically compatible delivery vehicle to give optimal release and uptake to the sites of action in a biologically active form during its time of application. In principle, antiplaque activity may be enhanced by combining antimicrobial agents with broadly similar, but complementary, modes of action. Alternatively, the activity of a single agent may be increased by use of a retention aid to enhance oral substantivity. Substantial evidence exists to demonstrate the validity of the first approach. However, there are few data, as yet, to support the effectiveness of the second. The oral mucosa is the bulk retention site for all clinically proven antiplaque agents. Plaque, the pellicle-coated tooth surface, and saliva are probably all sites of biological action. A detailed understanding of the interactions between agents and the various receptor sites, and of the importance ofthese receptor sites to biological activity, is generally lacking.
principles governing the oral delivery and clearance of antiplaque agents and the properties of dentifrices relating to their role as delivery vehicles; (iii) to review oral substantivity and clinical data for specific antiplaque agents; and (iv) to identify generic routes to enhance antiplaque efficacy and to review evidence for their effectiveness in vivo. Thus, it is intended to provide a view ofthe current state of knowledge and understanding of the delivery, substantivity, and mechanisms of retention of antiplaque agents from dentifrices, gels, and mouthrinses and the importance of these considerations to efficacy.
The key biological properties of antiplaque agents.
An antiplaque agent for use as a routine aid to mechanical oral hygiene procedures should possess the following properties: inherent biological activity consistent with its specific mode of antiplaque action, good oral substantivity, low toxicity, and low permeability. Each has a role in determining the dose, frequency of use, and delivery route of the agent. Antiplaque activity may be achieved in various ways. These include reducing the adhesion of bacteria to the tooth surface, inhibiting the growth and proliferation of micro-organisms on the tooth surface, inhibiting the formation of the intercellular plaque matrix, modifying plaque biochemistry to reduce the formation of cytotoxic products, and modifying plaque ecology to a less pathogenic flora (Cummins, 1991a). To function effectively as an antiplaque agent in vivo, an agent must be delivered to its site or sites of action in a biologically active form during the time of application, and it must be retained there for a sufficient period to exert its biological effect (Gjermo et al., 1970; Goodson, 1989; Van der Ouderaa and Cummins, 1989). The most successful antiplaque approach, to date, has been J Dent Res 71(7):1439-1449, July, 1992 the use of broad-spectrum antimicrobial agents such as chlorhexidine, metal ions, and phenolic compounds, which are subIntroduction. stantive to oral surfaces (Cummins, 1992). The efficacy of such agents is generally believed to result from the slow release of Supragingival plaque formation and the onset of early periodontal bound agent from these oral surfaces to give a level in saliva disease can be successfully controlled by scrupulous mechanical capable of inhibiting bacterial growth and, hence, plaque accuoral hygiene procedures (Lindhe and Nyman, 1975; Axelsson and mulation for an extended period between applications. A typical Lindhe, 1978;Abdellatif and Burt, 1987;Attstr6m, 1988). However, substantivity profile is illustrated in Fig. 1. In contrast, agents the dedication and motivation required to achieve such control is not which are antibacterial but which are not substantive are able the norm for most individuals. A typical response to prophylaxis, to act for only a relatively short time period after application, brushing instruction, and motivation is a temporary improvement with the result that the bacterial population is able to recover in gingival health which is lost in the absence of further motivation rapidly to normal levels, and plaque growth is unaffected. A (Svatunetal., 1990; Stephenetal., 1990). There is, therefore, a clear profile typical of a non-substantive agent is also illustrated in rationale for the use of antiplaque agents to augment mechanical Fig. 1. oral hygiene procedures (Kornman, 1986; Newman, 1986; Mandel, Although this representation is useful (see, for example, 1988; Van der Ouderaa, 1991). Goodson, 1989), a number of additional considerations should be In principle, a dentifrice provides an excellent vehicle for the borne in mind. First, this mechanism ignores the role of antidelivery of antiplaque agents because, in many societies, the ha- plaque agent bound to tooth surfaces in preventing plaque growth bitual use of a dentifrice is part ofnormal daily hygiene. In practice, on these surfaces and that bound to the plaque itself. Second, however, few agents have been successfully formulated to give the minimum inhibitory concentration (MIC) of an agent in the clinically active products (Kornman, 1986; Van der Ouderaa, 1992). mouth may be quite different from that normally measured in The aims of this paper are: (i) to summarize briefly the key vitro in broth culture. Clear differences in MIC's have been biological properties of antiplaque agents; (ii) to discuss the demonstrated for agents measured in broth culture and in saliva in vitro (Roberts and Addy, 1981), presumably due to differing Presented at the symposium on "New Agents in the Chemical Control of interactions with proteins (Hjeljord et al., 1973). Finally, growth Plaque and Gingivitis", during the IADR's 69th General Session, April 17, of bacteria may be retarded at concentrations well below the MIC (at which growth is stopped) of any given agent (Marsh, 1991). 1991, Acapulco, Mexico 1439
J Dent Res July 1992
CUMMINS & CREETH
1440
TABLE la SUMMARY OF PUBLISHED ORAL SUBSTANTIVITY DATA FOR CATIONIC ANTIMICROBIAL COMPOUNDS
Agent (vehicle) Chlorhexidine (mouthwash)
Total retention (%) 32 (pH 6.4)
Chlorhexidine (Gel)
32
References Bonesvoll et al., 1974a Bonesvoll and Gjermo, 1978 Bonesvoll et al., 1974a Bonesvoll, 1977a
Cetylpyridinium chloride (mouthwash)
65
Bonesvoll and Gjermo, 1978
Hexadecyl trimethyl ammonium bromide (mouthwash)
70
Bonesvoll and Gjermo, 1978
Sanguinarine (mouthwash) ND = Not determined. n= number of participants.
ND
Southard et al., 1984
12 (pH 3)
Thus, it is difficult to estimate a meaningful concentration above which antimicrobial activity of an agent is manifest in vivo (cf Goodson, 1989). Even though the relative activities ofthese substantive, broadspectrum, antimicrobial agents vary widely, they all appear to act multifunctionally to reduce bacterial adhesion, growth, and metabolism and, hence, to reduce plaque mass and plaque pathogenicity (Cummins, 1992). The oral mucosa has a low permeability barrier and is, therefore, an efficient tissue for the absorption of topically applied agents. As a result, antiplaque agents which are intended for topical delivery must have low acute and chronic toxicity and, preferably, low permeability (Goodson, 1989). Most of the topically applied antiplaque agents which are currently in use-such as chlorhexidine, quaternary ammonium compounds (Goodson, 1989), metal ions, and Triclosan (De Salva et al., 1989)-satisfy these criteria.
Ginneken, 1977). Hence, the retention of an agent is concentration-driven. The initial retention and distribution of an antiplaque agent within the oral cavity are determined by the strength (K1, etc.) and the rate of formation (kal, etc.) ofthe interactions between the agent and its various receptor sites (Fig. 3) and their accessibility. Current antiplaque agents appear to adhere to all surfaces within the mouth: the tooth pellicle, the oral epithelia (including the buccal mucosa, gingival tissues, and tongue), and supragingival plaque. Depending upon the specific mode of action of the antiplaque agent, these various receptor sites will be either sites of biological action or reservoirs (Goodson, 1989), as illustrated in Fig. 4. Saliva compositionwill influence oral speciation ifthe antiplaque agent binds to salivary protein, glycoprotein, or lipid via any of the interaction forces mentioned above. Clearance of an antiplaque agent from the mouth is controlled by the strength of binding (K1, etc.) and the rate of release (kbs, etc.) Principles of the delivery and clearance from the receptor sites (Goodson, 1989; Van der Ouderaa and of antiplaque agents in the mouth. Cummins, 1989). Saliva composition and salivary flow rate are key There are two sequential phases governing the oral retention of influences on these two factors. The kinetics of the clearance of nonan antiplaque agent: the release of the agent from the delivery binding substances from the mouth has been mathematically modvehicle and subsequent uptake of the agent to receptor sites. eled (Dawes, 1983) and subsequently extended to the clearance of Saliva may mediate between the delivery vehicle and the receptor substantive agents byuse ofsingle-reservoir (Gilbert, 1987; Goodson, sites, or the uptake may be direct, as depicted in Fig. 2. 1989) and double-reservoir (Wagner, 1975; Gilbert and Williams, The "release" phase is dependent on the diffusion coefficient 1987) models. It has been clearly demonstrated that individuals of the antiplaque agent from the vehicle during application. The vary substantially in the potential benefit they may attain from "uptake" to the receptor sites involves well-characterized physi- rinsing with an antiplaque agent, as a result of differences in their cochemical interactions, i.e., electrostatic, hydrophobic, and li- salivary flow rates (Goodson, 1989). Furthermore, elevated levels pophilic interactions, hydrogen bonding, and Van der Waals' of an antiplaque agent have been predicted to follow a night-time forces. Both phases are governed by first-order kinetics (Van rinse, due to low salivary flow rates during sleep (Goodson, 1989). Conc. of agent in saliva t\= < ~~Substantive
RELEASE PHASE
CLEARANCE PHASE
ISALIVA
DELIVERY VEHICLE
LOSS
(to or
\
IMinimum inhibitory
Non-substantive
I,/ agent
\
CLEARANCE PHASE
UPTAKE PHASE
concentration
Time-+ 1st dose
swallowing
expectoration)
2nd dose
Fig. 1-Hypothetical clearance curves for substantive and non-substantive agents from the oral surfaces.
ORAL RECEPTOR
SITES
Fig. 2-Model of the delivery and clearance of an antiplaque agent in the mouth.
Vol. 71 No. 7
DELIVERY OFANTIPLAQUE AGENTS
1441
TABLE lb PHARMACOKINETIC DATA CALCULATED FROM PUBLISHED DATA FOR CATIONIC ANTIMICROBIAL COMPOUNDS Dose Agent (vehicle)
(Ag)
Chlorhexidine (mouthwash) 20,000 7870 Cetylpyridinium chloride(mouthwash) Hexadecyl trimethyl ammonium 8010 bromide (mouthwash) Sanguinarine (mouthwash) 6740 x 2 = ND Not determined.
Total retention (%) 32
AO
kel
(iglg) 224
(min-') 0.0155
65
107
70
ND
Salivary flow rate has also been demonstrated to affect clearance of an unbound agent differentially according to its location within the mouth (LeComte and Dawes, 1987). It is likely, therefore, that clearance of a substantive antiplaque agent-whether from plaque, tooth pellicle, or oral mucosa-will be most rapid close to salivary ducts and slowest in the more stagnant areas of the mouth. This concept may have important implications for pharmacokinetic and clinical studies of antiplaque agents, but as yet it appears to have been largely ignored by researchers in these fields. The portion of the antiplaque agent which is retained in the oral cavity after application and which is available at the site or sites of action may be defined as the "bioactive" portion. This bioactive portion is by no means the total amount of the agent present, because the agent may be retained in irrelevant oral reservoirs which have no role in activity. It is the effect ofthis bioactive portion which, integrated over time, gives rise to clinical activity and, thus, should be maximized (Van der Ouderaa and Cummins, 1989). If there is no adsorption or binding of an agent within the oral cavity, then the agent must possess sufficient biological activity to be clinically effective within the short time [< 15 min (Dawes, 1983)] that it is present in the mouth. In practice, there are few examples of agents in this category.
General factors governing the delivery of an antiplaque agent to and its clearance from the oral cavity. Solubility.-Classically, an antiplaque agent must be solubilized in its delivery vehicle so that rapid release into the oral environment occurs, particularly when the application time is short. The digluconate salt of chlorhexidine, for instance, was selected for the development of chlorhexidine mouthrinses due to its high aqueous solubility (Senior, 1972). Similarly, Triclosan (2,4,4'-trichloro-2 hydroxydiphenyl ether), which has poor aqueous solubility, is solubilized in the flavor/surfactant phase of a dentifrice (Lane et al., 1985) which facilitates its release and retention during application (Gilbert, 1987; Gilbert and Williams, 1987). The solubility ofan agent does not solely determine its bioactivity, however. Stabilizing an agent in solution may diminish its tendency to adsorb onto the oral surfaces, because its chemical potential is reduced. This may occur for metal ions, for example, by complexation with ligands (Cummins and Watson, 1989). Similarly, this may occur for sparingly soluble organic species by interaction with the surfactant or flavor oils (Lane et al., 1985). The balance between solubility and stability in solution, on the one hand, and bioavailability, on the other, is very important to the degree of clinical benefit achievable. An alternative approach to effect delivery is to deposit an antiplaque agent in the form of sparingly soluble particles within the oral cavity such that they deliver low doses of the agent over a
0.0186
AUC [ig (%)] 7226 (36) 2876(36)
Bonesvoll and Gjermo, 1978 Bonesvoll and Gjermo, 1978
158
0.0226
3496 (44)
Bonesvoll and Gjermo, 1978
1.48
0.014
53 (
