S. P. Vyas, Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr H. S. Gour University, Sagar (M.P.) 470 003, India. Fax: + 91 7582 26525; E-mail: firstname.lastname@example.org
Advances in the understanding of the aetiology, epidemiology, pathogenesis and microbiology of periodontal pocket flora have revolutionized the strategies for the management of intraperiodontal pocket diseases. Intra-pocket, sustained release, drug delivery devices have been shown to be clinically effective in the treatment of periodontal infections. Several degradable and non-degradable devices are under investigation for the delivery of antimicrobial agents into the periodontal pocket including non-biodegradable fibres, films (biodegradable and non-biodegradable), bio-absorbable dental materials, biodegradable gels/ointments, injectables and microcapsules. With the realization that pocket bacteria accumulate as biofilms, studies are now being directed towards eliminating/killing biofilm concentrations rather than their planktonic (fluid phase) counterparts. Intraperiodontal pocket drug delivery has emerged as a novel paradigm for the future research. Similarly, bioadhesive delivery systems are explored that could significantly improve oral therapeutics for periodontal disease and mucosal lesions. A strategy is to target a wide range of molecular mediators of tissue destruction and hence arrest periodontal disease progression. Research into regenerating periodontal structures lost as a result of disease has also shown substantial progress in the last 25 years.
Dental diseases are recognized as a major public health problem throughout the world. Dental diseases are common in all age groups, ethnicities, races, genders and socioeconomic level ( 1). Numerous epidemiological studies show that dental diseases, tooth decay and diseases of periodontium are among the most common afflictions of mankind.
Periodontal disease is a collective term for a number of pathological conditions characterized by inflammation and degeneration of the gums (gingiva), supporting bone (alveolar bone), periodontal ligament and cementum. Periodontitis is an inflammation of the supporting tissue surrounding teeth caused by anaerobic bacteria and in the diseased state, supporting collagen of the periodontium is destroyed and the alveolar bones begin to resorb. The epithelium of the gingiva migrates along the tooth surface forming ‘periodontal pockets’ that provide an ideal environment for the growth and proliferation of microbes ( 2). More severe stages of the disease lead to the loosening and ultimately loss of teeth. The importance of bacteria in the aetiology of periodontitis has been clearly established and the treatment is directed towards controlling the bacterial flora in the periodontal pocket ( 3).
Many of the older classifications of periodontal disease included all types and considered them in terms of their pathological changes as inflammatory, degenerative or neoplastic ( 4). The most common disease is initiated by plaque accumulation in the gingivodental area and is basically inflammatory in character. Initially, it is confined to gingiva and is called chronic marginal gingivitis; later the supporting structures become involved, and the term marginal periodontitis is used to describe the disease. The term chronic destructive periodontitis, however, is a more accurate designation for the intraperiodontal diseases in general ( 5). The periodontal tissue can also be involved by other nosologic entities, unrelated to plaque, and many of these fall into the degenerative or neoplastic categories. They are considered as periodontal manifestations of systemic disease ( 4).
The aetiological profile of gingivitis has been attributed to local and systemic factors, the alterations in which may lead to the disease (Fig. 1). The local and systemic factors are interrelated ( 6). However, generally local factors are related to the immediate environment of the periodontium, whereas systemic factors pertain to the general condition of the patient. Local factors cause inflammation, the principal pathologic manifestation of periodontal disease. The systemic factors however, alter tissue response and as a result the effect of local irritants may be aggravated.
Local factors contributing to the pathogenesis include microorganisms, calculus (tartar), food impaction, mouth breathing, tooth malposition, faulty or irritating restorations or appliances and chemical or drug use (e.g. dilantin).
Systemic factors may contribute to the spread of intraperiodontal disorders. These include nutritional disturbances, drug action, allergy, psychic phenomena, neutrophil dysfunction, immunopathies, specific granulomatous infections and some endocrine dysfunctions like pregnancy and diabetic disorders.
Virulence factors may also lead to the pathogenicity of the disease. Collagenase and other enzymes originating from bacteria can destroy the connective tissue and ligament of the periodontium. Toxins of the bacteria contribute to the progress of periodontal disease ( 7). Bacteria and their metabolites or by-products may act as chemotactic agents, leading to migration of polymorphonuclear cells, evoking an inflammatory response by activating the immunological system ( 8).
Epidemiology and prevalence of periodontal pocket diseases and gingivitis
Epidemiological surveys conducted in various parts of the world show the universal distribution of caries and periodontal diseases. Epidemiological indices quantitatively explore clinical conditions on a graduated scale, thereby facilitating comparisons among populations for the prevalence or incidence of the pocket diseases ( 6). The epidemiological indices are based on various pathological manifestations encountered during infections. Clinical indices that are commonly adopted in periodontology are based upon the degree of pathogenicity of the periodontal tissues ( 6). For example, indices are used to assess gingival inflammation (periodontal index, gingival index, gingival bleeding index, etc.), the degree of periodontal destruction (gingival sulcus measurement component of the periodontal disease index), and the amount of plaque accumulated or the amount of calculus present. Gingivitis has been observed in children younger than 5 years of age. The highest prevalence of gingivitis occurs during puberty (12–17 years of age) and gradually decreases. However, it remains relatively high throughout the entire life. Adults (18–64 years of age) were found to be prone to periodontal diseases with or without intraperiodontal pockets ( 6, 9, 10). The age group that appears to be most affected by juvenile periodontitis is between puberty and approximately 30 years of age. Data from the National Health and Examination Survey (NHES), the National Health and Nutrition Examination Survey (NHANES) and the Hispanic Health and National Examination Survey (HHANES) reveal that the prevalence of periodontal disease increases directly with increasing age ( 6, 11). In general, males consistently have a higher prevalence and severity of periodontal disease than females. As far as geographical distribution is concerned it was concluded that compared with South America and the Asian countries, the prevalence and severity of periodontal pocket diseases in the U.S.A. is relatively low ( 10, 11).
Periodontal disease as an infection. Most forms of gingivitis and periodontitis are caused primarily by bacteria that colonize the gingival crevice and attach to intraperiodontal pockets ( 12). The omnipresence of many varieties of oral microorganisms growing as a film (bacterial biofilm) of plaque, for the most part on the non-self-cleansing areas of the teeth below the cervical convexity, has been recognized. Biofilms originate either from the normal gingival sulcus in case of marginal periodontitis, or from the gingival pocket in advanced periodontal disease ( 5, 13, 14). All reveal microorganisms of many different types. The composition of bacterial plaque associated with gingival health differs from that of plaque associated with the different periodontal diseases. In general, gram negative, facultative, anaerobic microorganisms are the principal bacteria associated with the periodontal diseases ( 13). Prominent among these are Bacteroids species, such as B. gingivalis and B. intermedius, Fusiform organisms, Actinobacillus actinomycetemcomitans, Wolinella recta, Eikenella species, various cocci and bacilli, sprirochetes and, in advanced periodonitis, amoebas and trichomonads ( 2, 6, 15). The normal oral flora is vast, however, making it impossible to prove conclusively that a particular type of microorganism is responsible for the pathogenesis of a specific periodontal disease. The flora is typically characterized by a predominance of gram-negative anaerobic rods. In juvenile periodontitis, gram-negative anaerobic rods increase in the areas of the deep pockets. A similar increase also occurs in the percent count of Actinobacillus actinomycetemcomitans and Capnocytophaga sputigena ( 6, 15, 16).
The periodontal pocket. A periodontal pocket is a pathologically dependent gingival sulcus and is one of the important clinical features of periodontal disease. Progressive pocket formation leads to destruction of the supporting periodontal tissues and loosening or exfoliation of the teeth. Microorganisms and their products that produce pathological tissue lead to the deepening of the gingival sulcus and create periodontal pockets. Pocket formation starts as an inflammatory process in the connective tissue wall of the gingival sulcus due to bacterial plaque ( 12, 17, 18, 19) (Fig. 2). Changes involved in the transition from the normal gingival sulcus to the pathological periodontal pocket are associated with different proportions of bacterial cells in dental plaque. The cellular and fluid inflammatory exudes cause degeneration of the surrounding connective tissue, including gingival fibres. Two hypothesis have been proposed regarding the mechanism of collagen fibre loss from the local immune responses. Collagenase and other lysosomal enzymes from polymorphonuclear leucocytes and macrophages become extracellular and destroy gingival fibres ( 6, 7), or fibroblasts phagocytose collagen fibres by extending cytoplasmic processes to the ligament–cementum interface ( 6, 12). Leukocytes and oedema from the inflamed connective tissue infiltrate the epithelium lining in the pocket, resulting in varying degrees of degeneration and necrosis.
Microbiology of periodontal disease. Periodontal disease is now considered to be a group of diseases or infections. Each disease is associated with a different group of microorganisms. The resulting clinical signs and symptoms can be similar or unique. The mechanisms by which subgingival bacteria may contribute to the pathogenesis of periodontal disease are varied (Fig. 3). The periodonto-pathogens possess numerous factors that permit them to directly damage the periodontium or to indirectly trigger a pathologic host response. Figure 4 explains the possible pathogenic mechanisms.
Once periodontal disease or gingivitis with pocket formation occurs, therapy must be directed at controlling the interaction between the plaque bacteria and the host response. Elimination of the periodontal pocket and improvement in attachment level are the basic aims of the overall clinical regimen of periodontitis (Table 1).
Table 1. Intragingival microorganisms in human periodontal pocket diseases and therapeutic strategies
Cause-related therapy in periodontitis is aimed at the reduction or elimination of microbial pathogens. Periodontitis in general is associated with microflora, consisting of indigenous, exogenous or superinfecting organisms. The management of periodontal infections due to indigenous infections (endogenous or commensal infections) involves continual reduction of the bacterial load mainly by mechanical debridement. The management of exogenous infections (true infections) is based on adjunctive antimicrobial therapy, whereas super-infections (opportunistic infections) are managed with a combined approach consisting of conventional therapy and improvement of host or environmental factors ( 20).
Over the last three decades, treatment strategies have evolved to eliminate specific pathogens or suppress the destructive host response. Research indicates that chemotherapeutic agents such as antimicrobial agents and anti-metabolites can alter disease progression. Three types of delivery system have been investigated: systemic, local and controlled or sustained release.
Conventional therapy is directed almost entirely towards controlling bacteria. It relies on mechanical plaque control including oral hygienic procedures, mechanical debridement of the root surfaces and surgical techniques ( 20). The surgical procedures are based either on providing easier access for oral hygiene procedures to previously inaccessible sites, or to regenerate lost periodontal support, and eliminate the inaccessible periodontal pocket. The procedures are time consuming, require highly trained personnel to carry them out and result in varying amounts of discomfort to the patients. Therefore, the use of non-surgical therapy and drug delivery to control the plaque is an attractive alternative ( 18, 19).
CONVENTIONAL ANTIMICROBIAL THERAPEUTICS
Standard periodontal therapy includes scaling and root planing, curettage, flap surgery with and without bone grafts, root amputation, hemisections, occlusal adjustment, and strict plaque control ( 6). Conventional root planing and scaling relies on the mechanical debridement of tooth surfaces as the primary antimicrobial measure. Although scaling and root planing are moderately successful, the rate of recurrence of periodontitis is high and frequent visits to the periodontist are necessary. Therefore, chemotherapeutic treatment of the infection is desirable ( 21, 22). Improvement in the disease condition (pocket depth and attachment loss) and elimination of putative periodontal pathogens have been achieved through conventional debridement supplemented with systemic antimicrobial agents. Although systemic administration of antibiotics is useful, high oral doses are necessary to achieve effective concentrations in the gingival fluid. However, long-term use may lead to the development of resistant bacterial strains. These drawbacks have led researchers world-wide to focus on localized delivery of antibiotics directly at the diseased site ( 22–25). Local irrigation, such as mouthwashes, are ineffective due to inadequate drug penetration into the periodontal pockets. Although intrapocket irrigation is effective in controlling periodontal infection, patient compliance is poor ( 26). As a result of these limitations associated with conventional therapy, delivery systems for localized and prolonged administration of antibiotic/antimicrobial into the periodontal pocket have been investigated ( 22, 24, 25).
Systemic administration of antimicrobial agents
Antimicrobial agents have been used systemically in periodontal therapy for over 25 years based on reports that systemically administered antibiotics are excreted via the saliva and/or gingival fluid. In combination with treatment of the infected pockets, systemic antimicrobial agents may be of importance in one or the following ways:
• in reaching and killing bacteria that cannot be removed by scaling, root planing and curettage, e.g. bacteria that have penetrated into the tissues in advanced periodontitis or localized juvenile periodontitis.
• in conjugation with non-surgical therapy, reduction or elimination of the need for periodontal therapy ( 27). Once bacteria have been removed from the pocket, aggressive plaque repopulates the pocket within a few weeks if hygienic conditions are not maintained.
• enhancing new attachment and bone regeneration. The re-infection of the pocket area is probably one of the major factors working against new attachment. The maintenance of a non- infected area may favour the new attachment of tissues and is also likely to improve the chances for success of osseous and non-osseous grafts ( 28).
Although many periodontopathogens are susceptible to the imidazole analogues, tetracyclines, penicillin, erythromycin, spiramycin, amoxycillin, chlavulanic acid and clindamycin, at concentrations that can be achieved in body fluids, none could inhibit all bacteria currently implicated or suspected as aetiological agents in periodontal pathogenesis ( 25). Several susceptibility studies have demonstrated that tetracyclines are the most potent drugs against periodontal pathogens. Tetracycline (250 mg four times per day for 1 or 2 weeks), or possibly minocycline administration as an adjunct, has been advocated for the treatment of refractory periodontal therapy after non-surgical treatment ( 29). Minocycline or doxycyclines alone were found to be better suppressors of periodontopathic flora at low GCF levels than parent tetracyclines ( 30, 31). Imidazole derivatives, i.e., metronidazole, tinidazole and niridazole administered systemically (800 mg to 1000 mg per day for 2 weeks) suppress the growth of anaerobic flora, including spirocheates and result in disappearance of the clinical and histopathological signs of periodontitis ( 6). There are other reports of adjunctive therapy by single or combined antimicrobial agents but lack of suitable control groups make difficult assignment of any true benefit to such combined therapy regimens ( 32, 33). Systemic antimicrobial regimens which achieve effective GCF levels may lead to adverse effect which make them unacceptable.
Local administration of antibiotics and antimicrobial agents
Local delivery has the advantage over systemic therapy of possibly achieving higher concentrations of drug at the intended site of action using a lower dosage with an associated reduction in side- and toxic effects. The local delivery of antimicrobial agents into the periodontal pocket is considered to have excellent potential as an adjunct to traditional periodontal therapy. The following local delivery systems have been tried for different agents: dentifrices ( 34), mouthrinses ( 35, 36), dental gels ( 37, 38), irrigation devices ( 39–41) and professional administration into the pocket by means of syringes.
Mouthrinses and dentifrices. Many antimicrobial agents have been tried as mouth rinses in the control of periodontal diseases using clinical follow-up studies, but none has proved to be more effective than chlorhexidine in providing in-vivo localization ( 35). Even chlorhexidine does not reach the periodontal pocket when administered as a mouth rinse. Fluoride mouthrinses have also been advocated for plaque and gingivitis ( 36). Mouthrinses and dentifrices are inefficient because of the short period of contact of the drug with the tissues and the lack of penetration into the periodontal pocket.
Dental irrigations. There have been attempts to use oral irrigators to deliver antimicrobial agents into the pocket on a daily basis. Sub-gingival irrigation of chlorhexidine in this manner delays bacterial repopulation of the pocket ( 40). A chlorhexidine solution (400 ml of 0·02% chlorhexidine gluconate) applied daily with an oral irrigator provided additional reduction in subgingival microflora and complete reduction of dental plaque. Subgingival irrigation with amine fluoride-stannous fluoride gel has also been tested in different clinical studies ( 41). Routine hygiene coupled with daily subgingival irrigation has been claimed to be an excellent regimen for changing the subgingival area from a diseased to healthy state ( 39, 41, 42).
Dental gels. Dental gels allow more accurate dosing and longer duration of action and medication loss is reported to be less than mouthrinses and dentifrices. When local gel delivery of metronidazole (25%) was compared with subgingival scaling, there was a statistically different but clinically insignificant difference ( 37). Using the same delivery device but with a more robust randomized study design, the clinical and microbiological parameters were found to be vastly improved when compared to subgingival scaling ( 38). In similar studies, local subgingival delivery of minocycline HCl ointment and topical tetracycline pastes produced only small improvements in clinical and microbiological parameters ( 43, 44).
DRUG DELIVERY CONSIDERATIONS
Various types of drug delivery system have been proposed for gingivitis, e.g. injectable devices ( 45), gels and ointments ( 46, 47) and films ( 48), etc. There are many products available or investigated for the subgingival delivery of antibacterial agents (Table 22). They represent the initial steps that have been taken in the field of topical sustained release chemotherapy for the treatment and control of gingivitis. Intra-pocket, sustained release, drug delivery devices have been shown to be clinically effective in the treatment of periodontitis. Intra-pocket devices can be divided into two broad categories depending on whether they are biodegradable or not. Non-degradable devices have the advantage that the therapist controls the removal of the device and therefore has greater control over the time of exposure of the pocket to the drug. However, a non-degradable device left in situ beyond its period of therapeutic efficacy is a potential hazard in that it could result in a foreign body response or immune response. Conversely, a biodegradable, sustained release, drug delivery system which can be placed into the periodontal pocket to maintain therapeutic concentrations for prolonged periods would be advantageous. This is because in addition to improving patient compliance over systemic antibiotics, patients are not required to visit the periodontist to have these devices removed at the completion of therapy, thereby making them more cost effective.
Table 2. Studies of local drug delivery systems (LDDS) for the treatment of periodontal pocket diseases
Several degradable and non-degradable devices are under investigation (Table 2) for the delivery of antimicrobial agents into the periodontal pocket ( 55), for example, fibres (non-biodegradable), films (biodegradable and non-biodegradable), bioabsorbable dental materials, biodegradable gels/ointments, injectables and microcapsules (Fig. 5).
Reservoir delivery systems
The use of fibres, or thread-like devices, for the sustained release of drugs into the periodontal pocket was the first reservoir device introduced by Goodson et al. ( 53) using cellulose acetate dialysis tubing (diameter=250 μm) to deliver solid tetracycline hydrochloride into the periodontal pocket. An appropriate length of tubing was administered by placement at the opening of the periodontal pocket and application of gentle pressure to insert it below the gingival margin. The system showed some clinical effects but was unable to sustain therapeutic levels of the drug for sufficient time to be clinically useful ( 54).
Drug solutions have also been incorporated in the reservoir devices made up of dialysis tubes of cellulose acetate. Clinical use of fibres containing 20% v/v chlorhexidine gluconate ( 56) and 0·5% w/v metronidazole ( 42) has led to the reduction in the signs and symptoms of periodontal disease. The clinical improvements that resulted from use of the dialysis tubing delivery system may be attributed to the high initial concentration. Addy et al. ( 57) subsequently showed that chlorhexidine was released from reservoir fibres over 4 days in vitro and more than 95% of the drug release occurred in the first 24 h. As the drug was placed at effective levels for 24 h, placement of single tubing does not provide sufficient treatment to prevent pocket recolonization.
Matrix delivery systems
A number of polymers were investigated as matrices (monolithic) for the delivery of tetracycline to periodontal pockets ( 53). Fibres were prepared by heat extrusion of 25% w/w tetracycline hydrochloride in polyethylene, polypropylene, poly(ɛ-caprolactone), polyurethane, ethyl vinyl acetate or cellulose acetate propionate ( 55). Rapid release was observed from polyethylene and polyurethane fibres, with most of drug released within 24 h. Polypropylene, poly(ɛ-caprolactone) and cellulose acetate propionate fibres released only a small fraction of their drug load rapidly, and could not provide an extended release profile ( 53). Ethylene vinyl acetate fibres produced a sustained in vitro release over 9 days and was proposed as a suitable carrier for tetracyclin delivery in periodontal pocket diseases. These initial studies were followed by others, notably those of Goodson and coworkers ( 53, 54, 58, 59), which have led to the development of a commercial delivery system (Actisite, Alza Corporation, Palo Alto, CA) (Fig. 6). Two multicentre studies ( 60, 61) show that the treatment of periodontal pocket with this system resulted in significant reductions in pocket probing depths and bleeding on probing and significant increases in attachment levels compared to the other treatments tested. Goodson’s solution, which is now being developed by Alza Corporation under the name OnSite ( 62) is a polymeric fibre-type delivery device, containing an antibiotic that can kill the bacteria associated with periodontal disease. The fibre is tied round the tooth below the gingival margin, so that the periodontal pocket is packed with the drug releasing material. Some of the figures show an overlaying dressing or band to prevent dislodgement. Goodson’s recent work has used a fibre 20 cm or longer ( 17, 25). The intricacies of winding this quantity of fibre into place, keeping it in the pocket, and then removing it after 7–10-day period may limit wide acceptance by periodontists and their patients.
Films are matrix delivery systems in which drug is distributed throughout the polymer and release occurs by drug diffusion and/or matrix dissolution or erosion. This dosage form has several advantageous physical properties for intrapocket use ( 63). The dimensions and shape of the film can be easily controlled to correspond to the dimensions of the pocket to be treated. It can be rapidly inserted into the pocket with minimal discomfort to the patient. It can be inserted to the base of the pocket and be totally submerged. If the thickness of the film does not exceed approximately 400 μm, and its physical properties provide it with sufficient adhesiveness, it will remain submerged without any noticeable interference to the patient’s oral hygiene habits. Both degradable and non-degradable forms of films have been developed. Those that release drug by diffusion alone are prepared using water-insoluble non-degradable polymers ( 53, 57), whereas those that release by diffusion and matrix erosion or dissolution use soluble ( 64, 65) or biodegradable polymers in the matrix ( 66–70).
The first descriptions of an intra-pocket, non-biodegradable matrix delivery device appeared in 1982. Addy and coworkers ( 57) described the use of matrix films of polymethylmethacrylate (Orthoresin™) for the intra-pocket delivery of tetracycline, metronidazole and chlorhexidine. Self-polymerizing mixtures of the polymer, monomer, and the appropriate drug were cured, as sheets, under high pressure and then cut into suitable sized films. Studies showed that in vitro release profile and duration of release of drugs from acrylic films (10 × 1 × 0·5 mm) was dependent on the drug payload in the delivery system. The extent of in vitro release also depended on the nature of drug incorporated, with films containing 30% w/w chlorhexidine, tetracycline or metronidazole releasing 57·0, 40·0 and 96·6% of their drug load. They further described formulations delivering in vitro therapeutic levels of all three drugs over a 14-day period. Clinical and microbiological assessment of films containing 30% w/w drug have shown metronidazole containing strips to be more effective, but there has been no evaluation of in vivo release rates achieved in the gingival crevicular fluid ( 71, 72). In later studies they showed various degrees of clinical efficacy in vitro but these systems were found to be associated with a slower rate of relapse of clinical parameters and have not been developed for clinical use ( 72).
Ethylcellulose matrix films for intra-pocket drug delivery have been described ( 73). These films were made by casting ethanol or chloroform solutions of the polymer into molds and allowing the solvent to evaporate. The appropriate drug and plasticizing agent were incorporated into the solution prior to casting. The dried films (200–300 μm thick) were then cut into the required shapes. Films containing chlorhexidine ( 74) metronidazole ( 75), minocycline ( 76) and tetracycline ( 77) have been developed and tested to varying degrees. The release of the therapeutic agent from these films is dependent on the solvent used, the presence of a plasticizer, the nature and concentration of the drug in the film and on the physical dimensions of the film. Films cast from ethanol solutions containing 5% w/w chlorhexidine released 95% of the drug load over 10 days, whereas chloroform-cast films released 20% of drug load over a 205-day period ( 74). This could be ascribed to the differential solubility of the drug in the casting solvents. Drug release from chloroform-cast films was modified by the addition of polyethylene glycol to the formulation. Golomb et al. ( 75) described metronidazole-bearing films casted with PEG 3000 and concluded that the amount of crystalline water bound to the surface of the films increased with the inclusion of PEG. It was further suggested that enhanced release of drug was due to improved water binding to the surface of matrix films containing PEG. Stabholz et al. ( 78) assessed the efficacy of periodic treatment with chlorhexidine-containing films in a 2-year study of maintenance of periodontal pocket and its bacterial load. Treatment was shown to produce significantly lower incidence of bleeding on probing, pocket depths and attachment levels when compared to the conventional maintenance treatment ( 79).
The limitations of such delivery devices include the need for removal and replacement, as they did not degrade. Moreover, the drug load is released over 3 days. This meant that patients require repeated dental visits to complete treatment. On the other hand, less expertise is required than for scaling and plaque removal ( 79).
Degradable matrix films
Degradable delivery systems erode or dissolve in the gingival crevice so that removal after treatment is not required. Drug release occurs by erosion or dissolution and drug diffusion through the matrix. The contribution of each of these mechanisms to the overall rate of release can be varied. Sustained release profile can be engineered by appropriate manipulation of one or more release mechanisms.
A number of biodegradable polymers have been investigated for the delivery of antimicrobial agents in the treatment of periodontal diseases, including hydroxypropyl cellulose ( 64), polyesters ( 68, 80) and cross-linked collagens and protein films ( 20). Hydroxypropyl cellulose films containing chlorhexidine and tetracycline for intra-pocket drug delivery have been described ( 64). Release of the drug and dissolution of the polymer were found to occur over different time intervals. Device erosion is not the major mechanism responsible for initial drug release (nearly 80% in initial 2 h), but probably accounts for the more gradual release seen from the device from 2 to 24 h. Tetracycline levels of between 0·5 and 3·5 μg/ml were achieved in the gingival crevicular fluid 24 h after insertion of films containing 1% w/w tetracycline in hydroxypropylcellulose. Reduction in probing depth, plaque index, gingival index, gingival index rate of bleeding and Bacteroids asaccharolyticus were reported with use of chlorhexidine- (1% w/w) containing strips. A prolonged release of ofloxacin was obtained by incorporation of slowly soluble methacrylic acid copolymer S particles into hydroxypropyl cellulose films ( 65).
Collins et al. ( 68) developed a slowly biodegradable compact using polyhydroxybutyric acid to deliver tetracycline in the treatment of pocket diseases. A pseudo-zero order release profile of tetracycline in vitro was recorded over a 9-day period with nearly 50% of the drug load being delivered over that period. Deasy et al. ( 81) studied the effects of tetracycline hydrochloride and metronidazole released from 0·5-mm thick films formed by compacting a 15 mg mixture of the drug and polyhydroxybutyric acid in an infrared press. The in-vitro release rate of drug was found to be dependent on the drug load and the drug used. The films, although intact after 5 days in a buffer solution, became progressively more fragile with loss of mechanical strength. Clinically, films containing 25% of either drug were placed into pockets at 4-day intervals of 16 days and their effect compared to untreated control pockets. In general, improvement in both clinical and microbiological parameters was noted over the 16 days of treatment, with a return to control levels on cessation of treatment. No information was provided on the in vivo survival time of the film.
Amorphous poly(DL) lactic acid compacts of tetracycline were used for supergingival delivery in the treatment of gingivitis ( 81). Salivary tetracycline levels were maintained at greater than 1 μg/ml for 4 days and 0·5 μg/ml in the next 6-day period. However, the clinical parameters could not be maintained upon the completion of the therapy.
The biodegradable polyester poly(ɛ-caprolactone) has been tested in vitro as a matrix for sustained release delivery both as a fibre for the delivery of tetracycline and as a film for the delivery of chlorhexidine ( 80). Clinically the fibres released their tetracycline content very rapidly with a half-life of 11 h. In a further study Dunn and coworkers ( 82) used poly(ɛ-caprolactone) to coat fibres produced with poly(ɛ-caprolactone), hydroxypropyl cellulose and polyethylene glycol and found zero order release in vitro. They suggested that poly(ɛ-caprolactone) and hydroxypropyl cellulose were most suitable for use as inner core material as these fibres were flexible and offered the greatest potential for effective drug delivery.
Different types of collagen-based membranes have also been tested as degradable devices for local drug delivery. Cross-linked atelocollagen-bound protein (Byco™) has been investigated as possible carrier material for antibacterial agents in the management of periodontal pocket diseases ( 69). A degradable controlled release device based on a formaldehyde cross-linked Byco protein matrix containing chlorhexidine has been described ( 83). Byco protein is a hydrolysed gelatin of bovine origin. The release of chlorhexidine from this device and its dissolution in vitro were shown to be dependent on the degree of protein cross-linking. The nature of the chlorhexidine salt used also affected the release rate. Based on this study the Perio Chip (Perio Products Ltd, Jerusalem, Israel) has been developed for the controlled delivery of chlorhexidine subgingivally ( 63, 69, 83). This is a 5 mm × 4 mm × 0·3 mm film containing 2·5 mg of chlorhexidine gluconate. The cross-linked collagen films were shown to produce significantly higher improvements in the gingival index, pocket depth, incidence of bleeding on probing, density of subgingival microorganisms and spirochaetes for a period of 7 weeks with the maximum effects seen in the first 2 weeks ( 63). A collagen film containing 5% metronidazole was evaluated as an adjunct to scaling and root planing in a 3-month clinical trial ( 84). Apart from the dimension of the device (5 mm × 5 mm), no information was provided about the nature of the matrix, the release kinetics of the device or its degradability. These authors reported a significant adjunctive effect for the local metronidazole therapy on gingival index, bleeding on probing, probing pocket depth and attachment level when compared with scaling and root planing alone. Diplen-Denta biopolymer adhesive film with chlorhexidine has been used in for treating periodontal inflammation ( 85).
Injecting a delivery system into the pocket has a number of advantages. It is a relatively simple procedure with little or no associated discomfort. The initially fluid formulation, which is necessary for its use with a syringe, allows the formulation to gain access to the entire pocket ( 63). In order to be retained in the pocket the formulation would need to change into a sticky semi-solid or solid so as to prevent it from removal by the GCF flow.
Two different systems are commercially available. The first, a 2% Minocycline ointment (Dentomycin®, Cyanamid International, Lederle Division, Wayne, NJ and SunStar, Osajam, Japan), does not appear to have any sustained release properties. In one study this ointment was applied as an adjunct to scaling and root planing ( 86). The second system (Elysol®, Dumex, Copenhagen, Denmark) is a controlled release delivery system. The liquid phase of this formulation consists of a water-free mixture of melted glycerol mono-oleate and metronidazole benzoate to which a triglyceride, sesame oil, has been added to lower the melting point in order to improve the flow properties of the gel in the syringe ( 87). When the mixture comes into contact with water it sets in a liquid crystalline state. The formulation contains 25% metronidazole as 40% w/w metronidazole benzoate. The solubility of the drug and its concentration in the formulation influence its release profile. The matrix is degraded by neutrophils and bacterial lipases present in the GCF ( 87). Concentrations of 103–1297 μg/ml of metronidazole were recorded in inflamed pockets treated with this device, with effective doses being maintained for 24–36 h. Systemic levels of metronidazole between 0·2 and 1·3 μm/ml were measured after the administration of 29–103 mg of the gel ( 87). The recommended therapy is two separate applications into each pocket, one week apart ( 36). Clinical studies comparing this therapeutic approach alone, to scaling and root planing, indicate that the metronidazole gel results in reduction in probing pocket depth and bleeding on probing which are not significantly different from the results obtained with scaling and root planing ( 43). Some examples of products on the world market are presented in Table 3.
Table 3. List of commercial subgingival delivery systems
Microcapsules are being used for the delivery of encapsulated antibacterial agents in treating periodontal disease. These are dissolution-controlled polymeric reservoir devices, which may deliver their contents with a prolonged release profile in the salivary or crevicular fluid. Microcapsules prepared from lactic acid/glycolic acid copolymers have been proposed for delivery of tetracycline ( 66) and minocycline ( 88). Baker et al. ( 66) suspended tetracycline-containing microcapsules in a Pluronic F 127 gel. This material forms a gel at body temperature to hold the microcapsules in the periodontal pocket for the duration of the treatment. They showed that after administration of the gel containing microcapsules to periodontal pockets in monkeys, the concentrations in the gingival crevicular fluid could be maintained at effective levels for 3–4 days. By contrast, Lawter et al. ( 88), administered minocycline microcapsules in a dry state to periodontal pockets of beagle dogs, and showed that an effective minocycline concentration was maintained for nearly 2 weeks.
‘BIOABSORBABLE’ DENTAL MATERIALS
Several biodegradable dental materials are potential drug carriers for use in the intraperiodontal pocket ( 55). Larson et al. ( 67) investigated doxycycline-bearing bioabsorbable materials as possible drug carriers to eradicate pocket bacterial flora. These materials included a haemostatic gauze made up of oxidized regenerated cellulose (Surgicel), a collagen wound dressing (CollaCote) and a fibrin sealant (Tissell). Doxycycline was incorporated into Surgicel and CollaCote by equilibrium in a 2% solution for 24 h and into Tissel by preparation of 100 μl clots containing 2% doxycycline. These bioabsorbable materials were compared with doxycycline-bearing non-biodegradable polyethylmethacrylate films ( 57). Larson et al. ( 67), reported that the physical properties of the non-degradable polyethylenemethacrylate strips changed when incubated in serum. The surface of these films softened and dissolved slightly with the subsequent risk of evoking an inflammatory response. However, Surgicel films in 0·5 ml serum swelled and dissolved over 2-week period with no apparent risk of immunological consequences, owing to their bio-absorbable nature.
THE FUTURE OF CONTROLLED RELEASE DRUG DELIVERY
Using biodegradable or non-biodegradable polymers, controlled release delivery systems theoretically produce concentration profiles that are more constant and longer lasting than those of other systems ( 83, 89, 90). Furthermore, patient compliance can be maximized and systemic complications reduced. During the past two decades, numerous investigations have been conducted to evaluate the potential role of controlled drug delivery in periodontal treatment. These investigations fall into two distinct categories: those documenting release kinetics, and those documenting clinical effects ( 91). Many researchers have demonstrated that controlled delivery of antimicrobial agents such as tetracycline, metronidazole and chlorhexidine can be effective in reducing the signs of periodontitis. In addition, controlled delivery of antimicrobial agents can alter the periodontal flora with a decrease in total bacterial mass and pathogenic species. While future research will concentrate on developing more ideal and bio-friendly polymers and introducing novel agents, controlled delivery offers clinicians a potential adjunct or alternative to traditional treatments ( 17, 24, 55, 92–97).
TARGET ORIENTED INTRA-PERIODONTAL POCKET DRUG DELIVERY
Recognition of pocket bacteria as biofilm
There is great interest in the use of antimicrobial agents and antiseptics for the prevention and treatment of plaque-related oral diseases and many workers have reported the results of studies in which the minimum inhibitory concentrations of agents for cariogenic and periodontopathogenic bacteria have been determined ( 18–25). However, such data are relevant only to situations where the organisms of interest are in aqueous suspensions (fluid phase or planktonic), whereas in caries and inflammatory periodontal diseases the target organisms are in the form of biofilms, a form in which they behave very differently. The bacteria in biofilms bind together in a sticky web of tangled polysaccharide fibres. These connect cells and anchor them to a surface and to each other. Within this microcosm, anaerobic and aerobic bacteria can thrive alongside each other, sharing water passageways and a complex structure ( 98). The polysaccharide coating is like a coat of armour. Different types of bacteria may collaborate to make a bacterial biofilm (Fig. 7).
By 1990, researchers confirmed that biofilm bacteria are morphologically and metabolically distinct from free-flowing ones, and that any bacterium can form a biofilm, once it finds a place to stick, as mostly provided by the mucosal layers underlining different peripheral organs ( 99). Adhesion to the bio-surface sets off a genetic cascade that turns on specific genes to make polysaccharides and/or to express surface receptors needed to establish the biofilm.
The resistance of these biofilms to antimicrobial agents is phenomenal. Not only do biofilms resist antimicrobials, but they are also large enough to defeat the immune system. Researchers are investigating creative ways to conquer biofilms, from novel antibodies to use of novel vesicular systems. Devices for attacking biofilms that decay tooth (dental plaque is the most common biofilm) or cause periodontitis are being developed ( 100). Preventive and therapeutic regimens for biofilm control and elimination based on antimicrobial agents formulated in various conventional and local drug delivery devices are being evaluated ( 101–107). Targeting bacterial biofilms has had major attention over the years, but the study of local drug delivery systems in this appear of application is still in its initial stages.
Periodontal pocket (Biofilm) targeting using liposomal delivery systems
Intra-periodontal pocket drug delivery systems are highly desirable due to a potentially lower incidence of undesirable side-effects, improved therapeutic efficacy, easy application and increased patient compliance. They can be made biodegradable and non-immunogenic and cost effective ( 108–111). Among the various delivery systems directed against the intraperiodontal pocket flora, liposomal systems were found to be versatile in their disposition drug. Vesicular systems are designed to mimic the bio-membrane in terms of structure and bio-behaviour, and hence are investigated intensively for targeting bacterial biofilms ( 34, 108–115). Jones and Kaszuba ( 108) reported polyhydroxy–mediated interactions between vesicles, made up of phosphatidylinositol and bacterial biofilms. The targeting of vesicles to adsorbed films of bacteria was thought to be due to the interaction of the surface polymers of the bacterial ‘glyco-calyx’ with vesicles incorporating lipids with polyhydroxy head groups. Sanderson and Jones ( 109) reported adsorption of cationic vesicles over biofilms of skin associated bacteria Staphylococcus epidermidis, which have a negative charge. Succinylated Con A (sCon-A)-bearing liposomes (proteoliposomes) have been found to be effective for the delivery of triclosan, to biofilms of skin associated Staphylococcus epidermidis and Proteus vulgaris and the oral bacterium Streptococcus sanguinis ( 110). Triclosan is a very effective bactericide, which is only sparingly soluble in water but it is capable of being trapped in the liposomal bilayers. Even after very short exposures (in-vivo and in-vitro studies) the succinylated Con A-bearing vesicles are retained by the bacteria eventually delivering triclosan in the cellular interiors to cause selective targeting of the invading pathogens. The targeting was assessed by the apparent monolayer coverage of the biofilms by liposomes. The optimum levels of phosphatidylinositol and concanavalin-A were established using enzyme-linked immunosorbant assay (ELISA). Free triclosan under the same experimental conditions was significantly less effective. Others ( 111) have also studied surface-bound lectins (succinylated Con-A and wheat germ agglutinin, WGA) in their sensitivities towards various oral and skin-associated bacteria. The oral bacteria Streptococcus mutans and S. gordonii and the skin-associated bacterium Coryneform hofmanni were targeted with a succinylated Con-A-bearing proteoliposomes, while the skin-associated bacterium Staphylococcus epidermidis was targeted with WGA-bearing proteoliposomes. The potential of lectin-bearing liposomal systems as a targetting system for the control of dental plaque and gingivitis has been studied extensively by Jones and coworkers ( 34, 112, 113). In attempts to optimize targeting, Jones and associates ( 114) prepared liposomes of dipalmitoylphosphatidylcholine (DPPC) incorporating the cationic lipids steraylamine (SA), dimethyldioctadecylammonium bromide (DDAB) and dimethylaminoethane carbamoyl cholesterol (DCChol) and the anionic lipids dipalmitoylphosphatidylglycerol (DPPG) and phosphatidylinnositol (PI). The delivery of the lipophilic bactericide triclosan and the water-soluble chlorhexidine was studied for a number of liposomal compositions. The binding of liposomes to the target site was measured radiochemically using an appropriate radiolabelled phospholipid or by an ELISA using an antibody which was specific for the target surface. Targeting was most effective for the systems DPPC-Chol-SA (for both bactericides), DPPC-DPPG and DPPC-PI liposomes (for triclosan) when used against S. epidermidis and S. sanguis biofilms. Double-labelling using 14C-chlorhexidine and 3H-DPPC suggested that there was an exchange between adsorbed liposomes which had delivered bactericide to the biofilm and those in the bulk solution, implying a diffusion mechanism for bactericide delivery. Robinson and coworkers ( 115) reported further on the specificity and affinity of immunoliposomes for oral bacteria. Immunoliposomes were prepared using antibodies raised against an antigenic determinant on the cell surface of Streptococcus oralis in an investigation of their potential to reduce dental plaque. The anti-oralis immunoliposomes showed the greatest affinity for S. oralis, when targeted to a range of different oral bacterial biofilms. The immunoliposome targeting affinity for S. oralis was largely unaffected by the number of antibodies conjugated to the liposomal surface or by the net charge on the lipid bilayer. Recently, Vyas and coworkers (unpublished) suggested lectin–carbohydrate interaction mediated delivery of metronidazole against the bacterial flora in the periodontal pocket. Lectin (Con-A)-bearing liposomes inhibited bacterial growth possibly by interacting with the specific sugars expressed on cell surface glyco- calyx of invading pocket microorganisms.
BIOADHESIVE DELIVERY SYSTEMS AS NOVEL INTRA-POCKET DELIVERY DEVICES
Bioadhesive delivery systems may improve oral therapeutics for periodontal disease and mucosal lesions ( 116). Jones and coworkers ( 117) developed a bioadhesive semi-solid, polymeric systems based upon hydroxyethylcellulose (HEC) and polyvinylpyrrolidone (PVP) containing tetracycline for the treatment of periodontal diseases. The mechanical properties of each formulation (hardness, compressibility, syringeability, adhesiveness, elasticity and cohesiveness) were determined using texture profile analysis. These workers concluded that an optimal choice of bioadhesive formulation for use in periodontal disease will involve a compromise between achieving the necessary release rate of tetracycline and the mechanical characteristics of the formulation. These were the factors found to affect clinical efficacy and the ease of product application into the periodontal pocket. In order to exploit bioadhesion as a means of enhancing vehicle retention in the periodontal pocket, Needleman and coworkers ( 116, 118) investigated the possible role of this phenomenon to aid oral drug delivery. Chitosan, xanthan gum and poly(ethylene oxide) were selected as potential bioadhesive vehicles. Retention in the periodontal pocket was assessed by means of an insoluble fluorescein marker in eight patients, and to the oral mucosa by the retention of a small plastic film in 12 subjects. The results showed that fluorescein release from the periodontal pocket was significantly longer for chitosan than for other gels or a water control. By contrast, xanthan gum gave the most prolonged adhesion time on the oral mucosa (153·5 min), followed by poly(ethylene oxide) (89·3 min) and chitosan (42·6 min), and these times were all significantly different from each other (P < 0·05). The results suggest that the bioadhesive properties of an aqueous gel may be related directly to its retention both in the periodontal pocket and on the oral mucosa. Although there is keen interest in developing improved drug delivery devices to the periodontal pocket and oral mucosa, there are few reports which have examined the physical properties of gels and semi-solid formulations which favour retention and bioadhesion in situ. Hydration and rheological properties appear to be of prime importance in this context and Needleman and associates ( 118) correlated the measurement of these properties with observed bioadhesion, both in vitro and in vivo using chitosan, xanthan gum and poly(ethylene oxide) bioadhesive systems. Hydration rates with various media were determined in specially constructed cells. Rheological properties were measured using a controlled stress rheometer under carefully regulated conditions. These findings were also correlated with in vivo assessments in the periodontal pocket and oral mucosa. The results demonstrated that three formulations with different bioadhesive properties also possessed widely different physical characteristics. Hydration experiments indicated a direct relationship between the rate of hydration and bioadhesion or retention. Rheological studies suggested that possession of a gel structure could be an important determinant of retention where shear forces are present in vivo, e.g. the oral mucosa. Furthermore, these studies indicated that formulations that could demonstrate resistance to changes in rheological properties on hydration would also favour retention in situ. Physical characterization therefore appears to have an important place in screening polymeric bioadhesive formulations prior to clinical testing in the periodontal pocket and oral mucosa.
NEWER TECHNOLOGIES FOR PERIODONTAL DISEASE MANAGEMENT
The bacterial aetiology of periodontal disease revealed since 1970 has logically led to the use of systemically administered antimicrobial treatment. In the late 1980s the concept of locally delivering antimicrobial agents to the periodontal pocket was introduced. Chemotherapy has an important place in the management of chronic periodontal diseases but routine use must be considered as an overprescription of these valuable agents. Sustained or controlled release drug delivery systems have revolutionized the treatment of periodontal disease ( 92–97, 119–127). As new agents are introduced and better delivery systems for the periodontal pocket are developed, periodontal disease progression can be halted. By blocking inflammatory pathways important in periodontal tissue destruction the disease should be better controlled. Clinical trials of flubiprofen, naproxen and ketoprofen indicate that it is possible to slow periodontal disease progression with NSAIDs. These reduce tissue breakdown and promote healing, including bone regeneration ( 128). In addition, data from animal models indicate that chemically modified tetracycline acts as an inhibitor of collagenase and slows disease progression in animals. Research into regenerating periodontal structures lost as a result of disease has had a noteworthy record of progress in the last 25 years. Recently, biological modifiers are used or suggested to be used in therapies directed at regenerating periodontal pockets ( 129). Techniques that utilize bone grafts, root treatments, tissue guiding membranes or polypeptide growth factors have ably indicated that it is possible to regenerate new attachment structures in humans.
The future of periodontal therapy is bright. Future research will concentrate on developing more ideal polymers and introducing new agents. Controlled and novel drug delivery systems offer clinicians a potential adjunct or alternative to traditional treatments. Targeting biofilms (plaque) with specially engineered liposomal systems has attracted major attention in recent years. As investigators continue to unravel the mysteries of the embryonic development of the periodontium, the ability to predictably regenerate lost periodontal attachment structures is likely to become reality.