Drug Deliv. and Transl. Res. (2014) 4:295–301 DOI 10.1007/s13346-013-0171-x
REVIEW ARTICLE
A mini-review on novel intraperiodontal pocket drug delivery materials for the treatment of periodontal diseases H. Hau & R. Rohanizadeh & M. Ghadiri & W. Chrzanowski
Published online: 4 September 2013 # Controlled Release Society 2013
Abstract Periodontal disease is defined as chronic inflammatory condition characterized by the destruction of the periodontal tissues causing loss of connective tissue attachment, loss of alveolar bone, and the formation of pathological pockets around the diseased teeth. The use of systemic antibiotics has been advocated for its treatment, but concerns emerged with respect to adverse drug reactions and its contribution to bacterial resistance. Thus local drug delivery devices have been developed that aim to deliver a high concentration of antimicrobial drugs directly to the affected site, while minimizing drug’s systemic exposure. A burst release of antimicrobial agent from carrier, resulting in a short and inadequate exposure of bacteria residing in periodontal pocket to the agent, remains the main challenge of current local delivery systems for the treatment of periodontal disease. This review aims to investigate and compare different local antimicrobial delivery systems with regard to the treatment of periodontal disease. Keywords Periodontal disease . Local drug delivery . Antimicrobial agents . Polymer gel . Clay
Introduction Periodontal disease is defined as chronic inflammatory condition characterized by the destruction of the periodontal tissues causing loss of connective tissue attachment, loss of alveolar bone, and the formation of pathological pockets around the diseased teeth [1]. It is estimated that over 47 % H. Hau : R. Rohanizadeh (*) : M. Ghadiri : W. Chrzanowski (*) Faculty of Pharmacy, University of Sydney, Sydney NSW 2006, Australia e-mail: [email protected] e-mail: [email protected]
of adults over 30 years old have periodontitis [1]. Some of these diseases are caused by the accumulation of dental plaque that extends into the subgingival areas of the periodontium [2]. Dental plaque contains pathogenic bacteria that are responsible for the inflammation seen in these diseases. It is known that plaque growth and inflammation of gingival tissue (gingivitis) are strongly linked irrespective of age, gender, or ethnicity [3]. The clinical signs of periodontitis include changes in the morphology of the affected gingival tissue, which causes the formation of a periodontal pocket. If the disease is left untreated, it can cause loosening and loss of teeth [1]. Therefore, eliminating pathogenic microflora in the pocket can prevent the development of gingivitis and periodontitis in most cases. Current treatments of periodontal diseases: systemic versus local antimicrobial therapy Multiple strategies have been used, alone or in combination, to produce and retain an environment that discourage plaque growth. These include maintain a good oral hygiene, scaling, and root planing [4]. The colonization of pathogenic microorganisms in subgingival areas causes the formation of periodontal pockets due to the destruction of supporting connective tissue, alveolar bone, and the migration of gingival epithelium along the tooth surface [5]. Daily oral hygiene relies on patient adherence, and the hygiene techniques are unable to reach into the subgingival environment. It was found that the elimination or even adequate suppression of periodontopathic microorganisms in subgingival plaque is virtually impossible for the patient to achieve on their own [6]. The effectiveness of scaling and root planing has been proven to be effective, but have some limitations such as limited accessibility to the bacteria residing deep in the periodontal pocket [2] and dependent on the skill of the clinician [6].
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Systemically administered antibiotics have been promoted for the treatment of severe forms of periodontitis. However, concerns emerged with respect to hypersensitivity, gastrointestinal intolerance, and development of bacterial resistance [7]. The efficacy of a systemic antimicrobial therapy was also questioned due to the inability to achieve and maintain adequate concentration of antimicrobial agent at the periodontal site when a low dose of the agent is administered [7]. To counter this problem, researchers have investigated the use of local drug delivery systems that provide a more controlled and sustained release of antimicrobial agents to the immediate vicinity of the inflammation site. More importantly, a local drug delivery system can achieve and maintain a greater concentration of drug at the diseased area than possible with their systemic counterpart [8], preventing the side effects of antimicrobial therapy. Bacteria residing in a biofilm, such as plaque, are known to be extremely resistant to antimicrobial therapy, ranging from a twofold to 1,000-fold difference in susceptibility [9]. One possible reason can be the incomplete penetration of the antimicrobial agent into such biofilms [10], and therefore, the biofilm needs to be mechanically disturbed. The local antimicrobial therapy provides a higher drug concentration at the diseased site, with much lower total dose than is required in systemic case, minimizing the development of bacterial resistance [11]. Due to these desirable properties of local antimicrobial treatments of periodontal disease, new approaches have been developed in recent decades. Local drug delivery for the treatment of periodontitis: challenges While local drug delivery systems have a sound theoretical basis, they present their own challenges in the therapy of periodontitis. For the treatment of periodontitis, one of the main problems with the earlier generation of local drug delivery systems in the form of mouth rinses and dentifrices was that the antimicrobial agents had a limited ability to penetrate into the subgingival environment [11]. It has been estimated that gingival crevicular fluid in periodontal pockets have a turnover rate of 40 times per hour [12], which largely limits the concentration and exposure time of the drug to bacteria residing in periodontal pocket. Without a sufficient concentration and prolonged access to bacteria, antimicrobial agents cannot maximize their effect/outcome. More recent work in this area focus on the development of intrapocket delivery systems. The gingival crevicular fluid acts as a leaching medium for the release of the antimicrobial agent from the drug delivery device inserted into the periodontal pocket. These systems can be divided into two classes according to the duration of drug release [13]. Sustained release systems, which provide less than 24 h of drug delivery, while controlled delivery systems have a duration that exceeds 24 h. The systems are able to overcome the problem of
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accessibility to bacteria, but both sustained and controlled systems combat the challenge of short exposure time and low concentration of drug with varying degrees of success. The first sustained release system involved the use of cellulose acetate dialysis tubing that were loaded with tetracycline and placed in the cervix of teeth of patients [14]. The study demonstrated a rapid release of tetracycline, with 95 % of the loaded drug depleted in the first 2 h, while maintaining a concentration of 15 μg/ml of tetracycline in gingival fluid over 24 h [14]. Newer systems that took advantage of novel materials and preparation techniques have enabled the development of a controlled release system. For example, in a human study, Mundargi et al. [15] reported a 90 % release of doxycycline from the device over 11 days, maintaining an average concentration of 4–10 μg/ml in the gingival cervicular fluid. From this, the American Academy of Periodontology proposed that for a successful local drug delivery system for the treatment of periodontal disease, they must fulfill three criteria [13]. Firstly, the medication must reach its intended site of action. Secondly, it must maintain adequate concentration of the drug at the intended site, and thirdly, lasts for a sufficient duration of time to eliminate the bacteria. Intraperiodontal pocket therapy has been developed in numerous forms in the pursuit of finding the optimal formulation and form [2,4–7,11,13–25]. The earlier systems involve the use of polymer fibers, strips, films, and gels that contain, in most cases, tetracycline or chlorhexidine. The more novel approaches include microparticles, nanoparticles, reactive (or smart) gels, clays, and cements combined with tetracycline, chlorhexidine, metronidazole, and other drugs. All these systems may be classified as being biodegradable or nonbiodegradable. Nonbiodegradable systems require removal after completion of drug release, which may cause irritation and inflammation of the treated sites [7], so the development of biodegradable systems has been of higher interest. Periodontitis associated with infections by pathogens are among the most difficult to treat. To be effective, the intraperiodontal antimicrobial delivery system should reach invasive bacteria in the soft tissue wall of a periodontal pocket. This is still unclear and further investigations are required to demonstrate the penetration of locally released agents into the surrounding soft tissues. It should be also noted that locally delivered antimicrobial agents are most useful to treat local sites that continue to undergo periodontal breakdown. This literature review focuses on the novel or future delivery devices or materials for intraperiodontal pocket drug delivery, namely, smart gels, clays, and cements. Some of these materials are at early stage of development for this particular application, and their clinical relevance need to be proven. The review introduces these new materials and provides information and discusses on their development and possible future application as intraperiodontal pocket drug delivery systems.
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Smart gel Gel-based drug delivery devices have been investigated since the early 1990s. Oils, glycerides, and/or polymers in combination with other excipients were used to produce materials with the desired pharmacokinetic properties, including rheological properties, melting point, and ability to delay drug release, as well as biodegradability. Gels are rapidly degraded by physiological catabolic reactions, which decreases the risk of irritation or allergic reactions at the site of application [5]. A semisolid gel material has been developed by Heller et al. [26]. It was found that a highly stable polymer can be produced using hydrophobic poly(orthoesters) to protect the hydrolytically labile orthoester linkages. Furthermore, the erosion rate of the polymer, which is dictated by the hydrolysis rate of the orthoester linkage, can be altered by changing the pH at the polymer–water interface. This was achieved by incorporating a latent acid into the polymer backbone that releases the corresponding α-hydroxy acid and acts as a catalyst to control hydrolysis of the orthoester linkages. Another advantage of poly(orthoesters) is that the mechanical and thermal properties of the material can be adjusted using different poly(orthoesters). In vitro release of tetracycline for the gel [22] showed that a 20 % drug-loaded gel released 100 % of its drug content in approximately 15 days, indicative of its suitability for periodontal use (Fig. 1). The clinical study found that the gel was very well tolerated and shown to also maintain a drug concentration above the minimum inhibitory concentration (MIC) of 1 μg/ml for up to 11 days [27]. However, the retention of the gel in the pocket, as demonstrated by measurable levels of tetracycline in the periodontal pocket, was very poor. After 11 days of trial, only 2 of the 24 treated sites retained the gel, and the rest were dislocated
Fig. 1 In vitro cumulative release of tetracycline from a 1,10-decanediol based gel in phosphate buffer solution at pH 7.4 and 37 °C [27]
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from the site. Therefore, this delivery material was concluded to be a promising agent in the treatment of periodontal disease, if the retention property could be significantly improved. Ji et al. [28] reported on a thermo-sensitive gel formulated with chitosan, N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan chloride (HTCC) and α,β-glycerophosate (α,β-GP) loaded with 0.1 % chlorhexidine. This biodegradable gel remains liquid at room temperature, but reacts to physiological temperatures by turning into a gel. This thermosensitive property provides an easy method of administration to the periodontal pocket site as a liquid, while having the more desirable retention time of a gel. This gel takes advantage of chitosan, a natural polysaccharide with known biocompatibility and biodegradability, and combines it with glycidyltrimethylammonium chloride (GTMAC), which enhances chitosan’s water solubility, bioadhesive and antibacterial properties. It was found that gelling time was around 6 min at 37 °C. While release studies showed that 68 % of chlorhexidine was released from the gel in 18 h, it was also found that increasing concentrations of glycerophosate retarded the release of chlorhexidine. The concentration of chlorhexidine also affected the release rate, with higher concentrations being released faster. Therefore, while the release profile was relatively short, the concentrations of glycerophosate and chlorhexidine were seen as parameters that can be altered to control the release profile of chlorhexidine from the gel. The toxicology study performed on rats showed no signs of acute toxicity at doses larger than 285 times the clinical exposure to the gel. Importantly, it was found that the MIC of the chlorhexidine containing gel was approximately 20 % and 50 % of the MIC of an equal concentration chlorhexidine in solution and another identical gel without the HTCC, respectively. This can be an advantage of this gel formulation that may be exploited in the further development of thermosensitive gels. Another ‘smart’ gel formulation was investigated by Dabhi et al. [11]. This formulation reacts and transforms into a gel upon contact with cations, such as calcium, potassium, or sodium, which are present in subgingival fluid. The investigators produced ornidazole gels with lutrol F127 with and without gellan gum. Gellan gum is known to be effective at low concentrations in aiding formation of gels and is also used as a disintegrant and film-coating agent. The different formulations include gels comprised of gellan gum only, lutrol F127 only, and combinations of both. The gels are prepared by dissolving varying concentrations of the gellan gum and/or lutrol F127 in distilled water with preservatives (methylparaben and propyleparaben), disodium edentate, and ornidazole. The formulation with 0.8 w/v of gellan gum and 14 % w/v of lutrol F127 was found to be optimum. The most advantageous aspect of this formulation is that it showed immediate gelation when contacted with simulated saliva and was able to remain in gel form for an extended period of time, most likely due to the relatively high concentration of
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gellan gum. However, the other properties, namely, rheology, in vitro drug release and syringeability, had to be balanced as adjusting concentrations of the polymers often improves one property while worsening another. In the end, while this formulation displayed suitable physical properties to act as a periodontal drug delivery system, its loaded drug was almost totally depleted within 12 h under stirring at 37 °C and pH 6.8. It can be concluded that ‘nonsmart’ gels may be more easily formulated to produce superior release profiles, as they are not restricted to the use of materials with stimulus sensitive property. The short duration of release demonstrated by the smart gels is unlikely to produce significant clinical effects, although that is yet to be confirmed by in vivo studies. Retention capability the gel is nonoptimal due to its viscosity. This problem can be resolved by increasing the viscosity of the gel which will compromise syringeability. The smart gels are formulated in an attempt to possess desired syringeability and high viscosity when required. Another solution is by introducing bioadhesive materials or enhancing bioadhesive properties of the existing materials. Recently, an adjunct to conventional therapy in the treatment of chronic periodontal disease gel formulation with metronidazole benzoate (Colgate Elyzol) has been approved and is currently available in the market. Metronidazole is an antibiotic that is active against most of the organisms that are associated with periodontal disease: Bacteroides spp., Fusobacterium, Selemonas, Wolinelia, Spirochetes, and other obligate anaerobic organisms. Metronidazole does not affect aerobic bacteria. Furthermore, some of the facultatively anaerobic bacteria (Actinobacillus actinomycetemcomitans ) are sensitive to metronidazole at concentration of 25 % after local application. It has been reported that after the application of the metronidazole containing dental gel (25 %), the antibiotic concentrations of above 100 mg/ml were measured locally in the crevicular fluid for at least 8 h [29]. At 36 h, concentrations above 1 mg/ml were still detected. Metronidazole was released slowly from the dental gel with a bioavailability of about 70 %. The maximal plasma concentration is found after approximately 4 h. Systemic concentrations above 1.3 mg/ml have not been detected [29].
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Fig. 2 Cumulative drug release as a function of the square root of time from brushite cement containing 6, 9 and 12 wt.% chlorhexidine with line of best fit [36]
(CaHPO4⋅2H2O) [30]. This gives it the advantage of also being injectable and set in situ at the infected area. Moreover, one of the unique advantages of brushite cement is that it is biodegradable [30,31]. Brushite’s ability to control the release of gentamicin, chlorhexidine, and tetracycline for periodontal disease has been demonstrated in the past [32,33]. Studies by Young et al. [33] demonstrated that the addition of up to 9 % w/w of chlorhexidine had no significant effect on the setting kinetics of the cement (Fig. 2). In vitro release profile has shown that 60 % of loaded chlorhexidine was released within 24 h, while the entire drug cargo was released only after 2 weeks. It was also observed that doubling the drug concentration in the cement will double the amount of drug released in a given time period, meaning the cumulative release percentage was independent of the drug concentration (Fig. 2). It was concluded that the drug was entrapped into cement pores without causing changes to the cement chemistry
Cements There are many different forms of biocements for various applications, but calcium phosphate cements have gained particular interest as a local drug delivery material due to their superior biocompatibility. Many different subtypes of calcium phosphate cements exist, but it was found that brushite cements are more suitable for use in drug delivery due to multiple advantages. Brushite cement is initially produced as a moldable paste, but eventually solidifies to form a hard material composed mainly of dicalcium phosphate dihydrate
Fig. 3 Doxycycline hyclate release from brushite cement in phosphate buffer solution at 37 °C at pH 7.4 (adapted from Tamimi et al. [30])
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similar, showing an initial burst release of almost 50 % of its loaded drug within the first 5 h. This was attributed to the low pH of the cement during the first day of setting. Under acidic conditions, both the hyclate and the monohydrate forms are freely soluble, leading to both forms being released easily. After the initial 5 h, a much slower rate of release was observed and approximately 75 % of the total loaded drug was released by day 4. The relatively large difference in release duration of the abovementioned two cement systems seems to suggest that chlorhexidine is a much better candidate drug than doxycycline.
Fig. 4 Cumulative release of timolol from montmorillionite in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.4) at 37 °C±0.5 [37]
and that its release profile makes brushite cement a suitable periodontal drug delivery device; however, immediate release is a major limitation of the cements. Studies on doxycycline release from brushite cement for periodontal treatment showed that changes to pH (after 4 days) affect the release kinetics; hence, the reported data are limited to only a 4-day period [23] (Fig. 3). It was also found that doxycycline inhibits brushite crystallization. This was deemed as a positive effect as pure brushite cement had too short setting time that complicates its clinical use. In addition, doxycycline improved the mechanical properties of brushite because of calcium chelation. The release kinetics of the two salt forms of doxycycline (hyclate and the monohydrate) were
Fig. 5 The cumulative drug release of ibuprofen from montmorillonite at varying pH at 37 °C [38]
Biocompatible clay Clays have been commonly used as excipient as well as active substance in pharmaceutical products [17]. It is known that the administration of some drugs with clay products decreases their bioavailability. Due to its layered structure, clays can absorb water and form a soft material suitable for local drug delivery in periodontal pocket. Several clay materials have been investigated as a drug delivery device, but very few, if any, have investigated their use in delivery of antibiotics. Joshi et al. [34] investigated the release of timolol maleate from montmorillonite (MMT) clay. MMT clay belongs to the smectite group of clays; it was recognized to have large specific surface area and exhibit good cation exchange capacity as well as good drug loading capacity. Suitability of the clay for sustained release of timolol was investigated, and it was found that the release profile of the intercalated drug within MMT system was similar in both simulated gastric
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and intestinal fluid; 43 % and 48 % of the total loaded drug was released after 9 h in gastric and intestinal fluid, respectively, after which the release remained relatively constant (Fig. 4). The incomplete release of timolol was attributed to the ion-exchange release mechanism. This mechanism relies on the timolol leaching out of the clay and reaching a state of equilibrium in the dissolution medium. Moreover, electrostatic interactions between the cationic timolol and the anionic charges at the surface of the MMT may further hinder the release process. The combination of these two factors may be the reason why only less than 50 % of timolol was released from the MMT clay. Studies of MMT system with ibuprofen showed that a carboxylic anion group, such as the one present in ibuprofen, interacts strongly with hydroxyl groups present on the MMT clay [35,36], which contributes to the controlled release of the drug. The results of the release studies indicated that the release of ibuprofen was more rapid and extensive in higher pH, such as in simulated intestinal fluid, than in lower pH of simulated gastric fluid. Within 120 min, 15.2 % and 28.9 % of ibuprofen was released in pH 1.2 and pH 7.4, respectively (Fig. 5). The release at the end of 650 min was around 25 % and 43 % in gastric fluid and intestinal fluid, respectively. It was concluded that this difference in release was due to the relatively higher solubility of ibuprofen in higher pH. As ibuprofen is a weak acid with a pKa of 5.2, it solubilizes to a greater extent in more alkaline conditions than in acidic conditions. The influence of drug loading was found that with higher drug loading, the rate and extent of release was also significantly higher at both pH 1.2 and pH 7.4. In comparing the above-mentioned two clay systems, it can be seen that they demonstrate similar drug release profiles in simulated interstitial fluid, achieving approximately 45 % total drug release over 9 to 10 h. However, if the drug release profiles in simulated gastric fluid are compared, the timolol system released approximately half of its loaded drug, while the ibuprofen system only released approximately 25 % of its loaded drug. As mentioned above, the difference in release between the two pHs with the ibuprofen system may be due to its pKa. With a pK a of 5.2, the two different pHs alter the state of protonation of ibuprofen and thus its charge and solubility. Timolol, with a pK a of 9.4, would be mostly protonated and charged in the pH range of 1.2 to 7.4, giving it a constant solubility. This suggests that in formulating drug delivery using clay systems, both the acid/base property and the pKa of the drug are important considerations. Since the mean gingival fluid pH was found to be in the range of 7.6-8.1 [37], for basic drugs, it is advantageous for in vivo drug release if the pK a is 10.1 or higher. This will cause most drug molecules to be protonated and contain a charge that enhances solubility. On the other hand, it would be optimal for an acidic drug to have a pKa of around 5.6 or lower so that drug release is not compromised by changes in the pH of the gingival fluid.
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One of the main advantages of clay systems is that the manufacturing process, including the incorporation of the active drug, is a relatively quick and simple process. Moreover, the clay materials themselves are known to be biocompatible, resulting in minimal or no damage to the surrounding gingival tissue. While incomplete and short duration of drug release may limit the use of the clay-based systems in periodontal applications, however, by increasing the amount of drug loading to a sufficiently high content and/or by slowing the release process, clay-based systems may become a suitable candidate for potential use as a drug carrier for periodontal disease.
Summary While the gel, cement, and clay-based formulations are potential modalities to be used as a carrier in intraperiodontal pocket drug delivery for treatment of periodontal disease, the physicochemical properties of carrier as well as carrier–drug interactions still need to be optimized for this application. A burst release of drug, a slow and incomplete drug release, and the retention of material in periodontal pocket are still existing challenges; however, with ongoing research, the discovery of a drug delivery system for intraperiodontal pocket that possesses the required characteristics suitable is highly likely. For optimal use as a drug delivery system for treatment of periodontal disease, most current systems release drug at optimal concentration for 7–10 days; hence, burst release and short release times observed for cements and clays are the major limitations.
Conflict of Interest None
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REVIEW ARTICLE
A mini-review on novel intraperiodontal pocket drug delivery materials for the treatment of periodontal diseases H. Hau & R. Rohanizadeh & M. Ghadiri & W. Chrzanowski
Published online: 4 September 2013 # Controlled Release Society 2013
Abstract Periodontal disease is defined as chronic inflammatory condition characterized by the destruction of the periodontal tissues causing loss of connective tissue attachment, loss of alveolar bone, and the formation of pathological pockets around the diseased teeth. The use of systemic antibiotics has been advocated for its treatment, but concerns emerged with respect to adverse drug reactions and its contribution to bacterial resistance. Thus local drug delivery devices have been developed that aim to deliver a high concentration of antimicrobial drugs directly to the affected site, while minimizing drug’s systemic exposure. A burst release of antimicrobial agent from carrier, resulting in a short and inadequate exposure of bacteria residing in periodontal pocket to the agent, remains the main challenge of current local delivery systems for the treatment of periodontal disease. This review aims to investigate and compare different local antimicrobial delivery systems with regard to the treatment of periodontal disease. Keywords Periodontal disease . Local drug delivery . Antimicrobial agents . Polymer gel . Clay
Introduction Periodontal disease is defined as chronic inflammatory condition characterized by the destruction of the periodontal tissues causing loss of connective tissue attachment, loss of alveolar bone, and the formation of pathological pockets around the diseased teeth [1]. It is estimated that over 47 % H. Hau : R. Rohanizadeh (*) : M. Ghadiri : W. Chrzanowski (*) Faculty of Pharmacy, University of Sydney, Sydney NSW 2006, Australia e-mail: [email protected] e-mail: [email protected]
of adults over 30 years old have periodontitis [1]. Some of these diseases are caused by the accumulation of dental plaque that extends into the subgingival areas of the periodontium [2]. Dental plaque contains pathogenic bacteria that are responsible for the inflammation seen in these diseases. It is known that plaque growth and inflammation of gingival tissue (gingivitis) are strongly linked irrespective of age, gender, or ethnicity [3]. The clinical signs of periodontitis include changes in the morphology of the affected gingival tissue, which causes the formation of a periodontal pocket. If the disease is left untreated, it can cause loosening and loss of teeth [1]. Therefore, eliminating pathogenic microflora in the pocket can prevent the development of gingivitis and periodontitis in most cases. Current treatments of periodontal diseases: systemic versus local antimicrobial therapy Multiple strategies have been used, alone or in combination, to produce and retain an environment that discourage plaque growth. These include maintain a good oral hygiene, scaling, and root planing [4]. The colonization of pathogenic microorganisms in subgingival areas causes the formation of periodontal pockets due to the destruction of supporting connective tissue, alveolar bone, and the migration of gingival epithelium along the tooth surface [5]. Daily oral hygiene relies on patient adherence, and the hygiene techniques are unable to reach into the subgingival environment. It was found that the elimination or even adequate suppression of periodontopathic microorganisms in subgingival plaque is virtually impossible for the patient to achieve on their own [6]. The effectiveness of scaling and root planing has been proven to be effective, but have some limitations such as limited accessibility to the bacteria residing deep in the periodontal pocket [2] and dependent on the skill of the clinician [6].
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Systemically administered antibiotics have been promoted for the treatment of severe forms of periodontitis. However, concerns emerged with respect to hypersensitivity, gastrointestinal intolerance, and development of bacterial resistance [7]. The efficacy of a systemic antimicrobial therapy was also questioned due to the inability to achieve and maintain adequate concentration of antimicrobial agent at the periodontal site when a low dose of the agent is administered [7]. To counter this problem, researchers have investigated the use of local drug delivery systems that provide a more controlled and sustained release of antimicrobial agents to the immediate vicinity of the inflammation site. More importantly, a local drug delivery system can achieve and maintain a greater concentration of drug at the diseased area than possible with their systemic counterpart [8], preventing the side effects of antimicrobial therapy. Bacteria residing in a biofilm, such as plaque, are known to be extremely resistant to antimicrobial therapy, ranging from a twofold to 1,000-fold difference in susceptibility [9]. One possible reason can be the incomplete penetration of the antimicrobial agent into such biofilms [10], and therefore, the biofilm needs to be mechanically disturbed. The local antimicrobial therapy provides a higher drug concentration at the diseased site, with much lower total dose than is required in systemic case, minimizing the development of bacterial resistance [11]. Due to these desirable properties of local antimicrobial treatments of periodontal disease, new approaches have been developed in recent decades. Local drug delivery for the treatment of periodontitis: challenges While local drug delivery systems have a sound theoretical basis, they present their own challenges in the therapy of periodontitis. For the treatment of periodontitis, one of the main problems with the earlier generation of local drug delivery systems in the form of mouth rinses and dentifrices was that the antimicrobial agents had a limited ability to penetrate into the subgingival environment [11]. It has been estimated that gingival crevicular fluid in periodontal pockets have a turnover rate of 40 times per hour [12], which largely limits the concentration and exposure time of the drug to bacteria residing in periodontal pocket. Without a sufficient concentration and prolonged access to bacteria, antimicrobial agents cannot maximize their effect/outcome. More recent work in this area focus on the development of intrapocket delivery systems. The gingival crevicular fluid acts as a leaching medium for the release of the antimicrobial agent from the drug delivery device inserted into the periodontal pocket. These systems can be divided into two classes according to the duration of drug release [13]. Sustained release systems, which provide less than 24 h of drug delivery, while controlled delivery systems have a duration that exceeds 24 h. The systems are able to overcome the problem of
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accessibility to bacteria, but both sustained and controlled systems combat the challenge of short exposure time and low concentration of drug with varying degrees of success. The first sustained release system involved the use of cellulose acetate dialysis tubing that were loaded with tetracycline and placed in the cervix of teeth of patients [14]. The study demonstrated a rapid release of tetracycline, with 95 % of the loaded drug depleted in the first 2 h, while maintaining a concentration of 15 μg/ml of tetracycline in gingival fluid over 24 h [14]. Newer systems that took advantage of novel materials and preparation techniques have enabled the development of a controlled release system. For example, in a human study, Mundargi et al. [15] reported a 90 % release of doxycycline from the device over 11 days, maintaining an average concentration of 4–10 μg/ml in the gingival cervicular fluid. From this, the American Academy of Periodontology proposed that for a successful local drug delivery system for the treatment of periodontal disease, they must fulfill three criteria [13]. Firstly, the medication must reach its intended site of action. Secondly, it must maintain adequate concentration of the drug at the intended site, and thirdly, lasts for a sufficient duration of time to eliminate the bacteria. Intraperiodontal pocket therapy has been developed in numerous forms in the pursuit of finding the optimal formulation and form [2,4–7,11,13–25]. The earlier systems involve the use of polymer fibers, strips, films, and gels that contain, in most cases, tetracycline or chlorhexidine. The more novel approaches include microparticles, nanoparticles, reactive (or smart) gels, clays, and cements combined with tetracycline, chlorhexidine, metronidazole, and other drugs. All these systems may be classified as being biodegradable or nonbiodegradable. Nonbiodegradable systems require removal after completion of drug release, which may cause irritation and inflammation of the treated sites [7], so the development of biodegradable systems has been of higher interest. Periodontitis associated with infections by pathogens are among the most difficult to treat. To be effective, the intraperiodontal antimicrobial delivery system should reach invasive bacteria in the soft tissue wall of a periodontal pocket. This is still unclear and further investigations are required to demonstrate the penetration of locally released agents into the surrounding soft tissues. It should be also noted that locally delivered antimicrobial agents are most useful to treat local sites that continue to undergo periodontal breakdown. This literature review focuses on the novel or future delivery devices or materials for intraperiodontal pocket drug delivery, namely, smart gels, clays, and cements. Some of these materials are at early stage of development for this particular application, and their clinical relevance need to be proven. The review introduces these new materials and provides information and discusses on their development and possible future application as intraperiodontal pocket drug delivery systems.
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Smart gel Gel-based drug delivery devices have been investigated since the early 1990s. Oils, glycerides, and/or polymers in combination with other excipients were used to produce materials with the desired pharmacokinetic properties, including rheological properties, melting point, and ability to delay drug release, as well as biodegradability. Gels are rapidly degraded by physiological catabolic reactions, which decreases the risk of irritation or allergic reactions at the site of application [5]. A semisolid gel material has been developed by Heller et al. [26]. It was found that a highly stable polymer can be produced using hydrophobic poly(orthoesters) to protect the hydrolytically labile orthoester linkages. Furthermore, the erosion rate of the polymer, which is dictated by the hydrolysis rate of the orthoester linkage, can be altered by changing the pH at the polymer–water interface. This was achieved by incorporating a latent acid into the polymer backbone that releases the corresponding α-hydroxy acid and acts as a catalyst to control hydrolysis of the orthoester linkages. Another advantage of poly(orthoesters) is that the mechanical and thermal properties of the material can be adjusted using different poly(orthoesters). In vitro release of tetracycline for the gel [22] showed that a 20 % drug-loaded gel released 100 % of its drug content in approximately 15 days, indicative of its suitability for periodontal use (Fig. 1). The clinical study found that the gel was very well tolerated and shown to also maintain a drug concentration above the minimum inhibitory concentration (MIC) of 1 μg/ml for up to 11 days [27]. However, the retention of the gel in the pocket, as demonstrated by measurable levels of tetracycline in the periodontal pocket, was very poor. After 11 days of trial, only 2 of the 24 treated sites retained the gel, and the rest were dislocated
Fig. 1 In vitro cumulative release of tetracycline from a 1,10-decanediol based gel in phosphate buffer solution at pH 7.4 and 37 °C [27]
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from the site. Therefore, this delivery material was concluded to be a promising agent in the treatment of periodontal disease, if the retention property could be significantly improved. Ji et al. [28] reported on a thermo-sensitive gel formulated with chitosan, N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan chloride (HTCC) and α,β-glycerophosate (α,β-GP) loaded with 0.1 % chlorhexidine. This biodegradable gel remains liquid at room temperature, but reacts to physiological temperatures by turning into a gel. This thermosensitive property provides an easy method of administration to the periodontal pocket site as a liquid, while having the more desirable retention time of a gel. This gel takes advantage of chitosan, a natural polysaccharide with known biocompatibility and biodegradability, and combines it with glycidyltrimethylammonium chloride (GTMAC), which enhances chitosan’s water solubility, bioadhesive and antibacterial properties. It was found that gelling time was around 6 min at 37 °C. While release studies showed that 68 % of chlorhexidine was released from the gel in 18 h, it was also found that increasing concentrations of glycerophosate retarded the release of chlorhexidine. The concentration of chlorhexidine also affected the release rate, with higher concentrations being released faster. Therefore, while the release profile was relatively short, the concentrations of glycerophosate and chlorhexidine were seen as parameters that can be altered to control the release profile of chlorhexidine from the gel. The toxicology study performed on rats showed no signs of acute toxicity at doses larger than 285 times the clinical exposure to the gel. Importantly, it was found that the MIC of the chlorhexidine containing gel was approximately 20 % and 50 % of the MIC of an equal concentration chlorhexidine in solution and another identical gel without the HTCC, respectively. This can be an advantage of this gel formulation that may be exploited in the further development of thermosensitive gels. Another ‘smart’ gel formulation was investigated by Dabhi et al. [11]. This formulation reacts and transforms into a gel upon contact with cations, such as calcium, potassium, or sodium, which are present in subgingival fluid. The investigators produced ornidazole gels with lutrol F127 with and without gellan gum. Gellan gum is known to be effective at low concentrations in aiding formation of gels and is also used as a disintegrant and film-coating agent. The different formulations include gels comprised of gellan gum only, lutrol F127 only, and combinations of both. The gels are prepared by dissolving varying concentrations of the gellan gum and/or lutrol F127 in distilled water with preservatives (methylparaben and propyleparaben), disodium edentate, and ornidazole. The formulation with 0.8 w/v of gellan gum and 14 % w/v of lutrol F127 was found to be optimum. The most advantageous aspect of this formulation is that it showed immediate gelation when contacted with simulated saliva and was able to remain in gel form for an extended period of time, most likely due to the relatively high concentration of
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gellan gum. However, the other properties, namely, rheology, in vitro drug release and syringeability, had to be balanced as adjusting concentrations of the polymers often improves one property while worsening another. In the end, while this formulation displayed suitable physical properties to act as a periodontal drug delivery system, its loaded drug was almost totally depleted within 12 h under stirring at 37 °C and pH 6.8. It can be concluded that ‘nonsmart’ gels may be more easily formulated to produce superior release profiles, as they are not restricted to the use of materials with stimulus sensitive property. The short duration of release demonstrated by the smart gels is unlikely to produce significant clinical effects, although that is yet to be confirmed by in vivo studies. Retention capability the gel is nonoptimal due to its viscosity. This problem can be resolved by increasing the viscosity of the gel which will compromise syringeability. The smart gels are formulated in an attempt to possess desired syringeability and high viscosity when required. Another solution is by introducing bioadhesive materials or enhancing bioadhesive properties of the existing materials. Recently, an adjunct to conventional therapy in the treatment of chronic periodontal disease gel formulation with metronidazole benzoate (Colgate Elyzol) has been approved and is currently available in the market. Metronidazole is an antibiotic that is active against most of the organisms that are associated with periodontal disease: Bacteroides spp., Fusobacterium, Selemonas, Wolinelia, Spirochetes, and other obligate anaerobic organisms. Metronidazole does not affect aerobic bacteria. Furthermore, some of the facultatively anaerobic bacteria (Actinobacillus actinomycetemcomitans ) are sensitive to metronidazole at concentration of 25 % after local application. It has been reported that after the application of the metronidazole containing dental gel (25 %), the antibiotic concentrations of above 100 mg/ml were measured locally in the crevicular fluid for at least 8 h [29]. At 36 h, concentrations above 1 mg/ml were still detected. Metronidazole was released slowly from the dental gel with a bioavailability of about 70 %. The maximal plasma concentration is found after approximately 4 h. Systemic concentrations above 1.3 mg/ml have not been detected [29].
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Fig. 2 Cumulative drug release as a function of the square root of time from brushite cement containing 6, 9 and 12 wt.% chlorhexidine with line of best fit [36]
(CaHPO4⋅2H2O) [30]. This gives it the advantage of also being injectable and set in situ at the infected area. Moreover, one of the unique advantages of brushite cement is that it is biodegradable [30,31]. Brushite’s ability to control the release of gentamicin, chlorhexidine, and tetracycline for periodontal disease has been demonstrated in the past [32,33]. Studies by Young et al. [33] demonstrated that the addition of up to 9 % w/w of chlorhexidine had no significant effect on the setting kinetics of the cement (Fig. 2). In vitro release profile has shown that 60 % of loaded chlorhexidine was released within 24 h, while the entire drug cargo was released only after 2 weeks. It was also observed that doubling the drug concentration in the cement will double the amount of drug released in a given time period, meaning the cumulative release percentage was independent of the drug concentration (Fig. 2). It was concluded that the drug was entrapped into cement pores without causing changes to the cement chemistry
Cements There are many different forms of biocements for various applications, but calcium phosphate cements have gained particular interest as a local drug delivery material due to their superior biocompatibility. Many different subtypes of calcium phosphate cements exist, but it was found that brushite cements are more suitable for use in drug delivery due to multiple advantages. Brushite cement is initially produced as a moldable paste, but eventually solidifies to form a hard material composed mainly of dicalcium phosphate dihydrate
Fig. 3 Doxycycline hyclate release from brushite cement in phosphate buffer solution at 37 °C at pH 7.4 (adapted from Tamimi et al. [30])
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similar, showing an initial burst release of almost 50 % of its loaded drug within the first 5 h. This was attributed to the low pH of the cement during the first day of setting. Under acidic conditions, both the hyclate and the monohydrate forms are freely soluble, leading to both forms being released easily. After the initial 5 h, a much slower rate of release was observed and approximately 75 % of the total loaded drug was released by day 4. The relatively large difference in release duration of the abovementioned two cement systems seems to suggest that chlorhexidine is a much better candidate drug than doxycycline.
Fig. 4 Cumulative release of timolol from montmorillionite in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.4) at 37 °C±0.5 [37]
and that its release profile makes brushite cement a suitable periodontal drug delivery device; however, immediate release is a major limitation of the cements. Studies on doxycycline release from brushite cement for periodontal treatment showed that changes to pH (after 4 days) affect the release kinetics; hence, the reported data are limited to only a 4-day period [23] (Fig. 3). It was also found that doxycycline inhibits brushite crystallization. This was deemed as a positive effect as pure brushite cement had too short setting time that complicates its clinical use. In addition, doxycycline improved the mechanical properties of brushite because of calcium chelation. The release kinetics of the two salt forms of doxycycline (hyclate and the monohydrate) were
Fig. 5 The cumulative drug release of ibuprofen from montmorillonite at varying pH at 37 °C [38]
Biocompatible clay Clays have been commonly used as excipient as well as active substance in pharmaceutical products [17]. It is known that the administration of some drugs with clay products decreases their bioavailability. Due to its layered structure, clays can absorb water and form a soft material suitable for local drug delivery in periodontal pocket. Several clay materials have been investigated as a drug delivery device, but very few, if any, have investigated their use in delivery of antibiotics. Joshi et al. [34] investigated the release of timolol maleate from montmorillonite (MMT) clay. MMT clay belongs to the smectite group of clays; it was recognized to have large specific surface area and exhibit good cation exchange capacity as well as good drug loading capacity. Suitability of the clay for sustained release of timolol was investigated, and it was found that the release profile of the intercalated drug within MMT system was similar in both simulated gastric
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and intestinal fluid; 43 % and 48 % of the total loaded drug was released after 9 h in gastric and intestinal fluid, respectively, after which the release remained relatively constant (Fig. 4). The incomplete release of timolol was attributed to the ion-exchange release mechanism. This mechanism relies on the timolol leaching out of the clay and reaching a state of equilibrium in the dissolution medium. Moreover, electrostatic interactions between the cationic timolol and the anionic charges at the surface of the MMT may further hinder the release process. The combination of these two factors may be the reason why only less than 50 % of timolol was released from the MMT clay. Studies of MMT system with ibuprofen showed that a carboxylic anion group, such as the one present in ibuprofen, interacts strongly with hydroxyl groups present on the MMT clay [35,36], which contributes to the controlled release of the drug. The results of the release studies indicated that the release of ibuprofen was more rapid and extensive in higher pH, such as in simulated intestinal fluid, than in lower pH of simulated gastric fluid. Within 120 min, 15.2 % and 28.9 % of ibuprofen was released in pH 1.2 and pH 7.4, respectively (Fig. 5). The release at the end of 650 min was around 25 % and 43 % in gastric fluid and intestinal fluid, respectively. It was concluded that this difference in release was due to the relatively higher solubility of ibuprofen in higher pH. As ibuprofen is a weak acid with a pKa of 5.2, it solubilizes to a greater extent in more alkaline conditions than in acidic conditions. The influence of drug loading was found that with higher drug loading, the rate and extent of release was also significantly higher at both pH 1.2 and pH 7.4. In comparing the above-mentioned two clay systems, it can be seen that they demonstrate similar drug release profiles in simulated interstitial fluid, achieving approximately 45 % total drug release over 9 to 10 h. However, if the drug release profiles in simulated gastric fluid are compared, the timolol system released approximately half of its loaded drug, while the ibuprofen system only released approximately 25 % of its loaded drug. As mentioned above, the difference in release between the two pHs with the ibuprofen system may be due to its pKa. With a pK a of 5.2, the two different pHs alter the state of protonation of ibuprofen and thus its charge and solubility. Timolol, with a pK a of 9.4, would be mostly protonated and charged in the pH range of 1.2 to 7.4, giving it a constant solubility. This suggests that in formulating drug delivery using clay systems, both the acid/base property and the pKa of the drug are important considerations. Since the mean gingival fluid pH was found to be in the range of 7.6-8.1 [37], for basic drugs, it is advantageous for in vivo drug release if the pK a is 10.1 or higher. This will cause most drug molecules to be protonated and contain a charge that enhances solubility. On the other hand, it would be optimal for an acidic drug to have a pKa of around 5.6 or lower so that drug release is not compromised by changes in the pH of the gingival fluid.
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One of the main advantages of clay systems is that the manufacturing process, including the incorporation of the active drug, is a relatively quick and simple process. Moreover, the clay materials themselves are known to be biocompatible, resulting in minimal or no damage to the surrounding gingival tissue. While incomplete and short duration of drug release may limit the use of the clay-based systems in periodontal applications, however, by increasing the amount of drug loading to a sufficiently high content and/or by slowing the release process, clay-based systems may become a suitable candidate for potential use as a drug carrier for periodontal disease.
Summary While the gel, cement, and clay-based formulations are potential modalities to be used as a carrier in intraperiodontal pocket drug delivery for treatment of periodontal disease, the physicochemical properties of carrier as well as carrier–drug interactions still need to be optimized for this application. A burst release of drug, a slow and incomplete drug release, and the retention of material in periodontal pocket are still existing challenges; however, with ongoing research, the discovery of a drug delivery system for intraperiodontal pocket that possesses the required characteristics suitable is highly likely. For optimal use as a drug delivery system for treatment of periodontal disease, most current systems release drug at optimal concentration for 7–10 days; hence, burst release and short release times observed for cements and clays are the major limitations.
Conflict of Interest None
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