|Year : 2012 | Volume
| Issue : 2 | Page : 200-206
The evaluation of doxycycline controlled release gel versus doxycycline controlled release implant in the management of periodontitis
Vandana Srikrishna Chadha1, Khandige Mahalinga Bhat2
1 Department of Periodontics, Manav Rachna Dental College, Faridabad, Haryana, India
2 CODS, Manipal, Karnataka, India
|Date of Submission||08-Aug-2010|
|Date of Acceptance||29-Dec-2011|
|Date of Web Publication||1-Aug-2012|
Vandana Srikrishna Chadha
M 43, Kalkaji, New Delhi 110 019
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Investigators have sought different methods to deliver antimicrobials to periodontal pockets. This study was designed to assess the efficacy of locally made doxycycline gel versus locally made doxycycline implant as biodegradable controlled local delivery systems, by evaluating the pharmacological drug release and improvement in gingival status, gain in attachment, and reduction in pocket depth. Materials and Methods: Thirty patients with localized periodontal pockets ≥5 mm were randomly divided into three groups. The first group received the doxycycline gel, the second the doxycycline implant, and the third received only scaling and root planing (the control group). The patients in the first two groups were selected for the drug release. Clinical parameters such as gingival index, plaque index, probing depth, and attachment levels were recorded at baseline and the 90 th day. Gingival crevicular fluid (GCF) and saliva samples were collected 1 hour following gel and implant placement and then on the 10 th , 30 th , and 60 th days. Results: There was a statistically significant difference in the release of doxycycline from the gel when compared with the implant in the GCF and saliva on the 10 th and 30 th days. All the three groups showed improvement in clinical parameters. The improvements in both gel and implant groups were greater when compared with the control group with no statistically significant difference between the implant and gel systems. Conclusion: The use of local delivery of doxycycline through gel and Implant media further enhances the positive changes obtained following scaling and root planing. The release of doxycycline from the implant and the gel was comparable.
Keywords: Local delivery systems, gel, implant, doxycycline, periodontitis
|How to cite this article:|
Chadha VS, Bhat KM. The evaluation of doxycycline controlled release gel versus doxycycline controlled release implant in the management of periodontitis. J Indian Soc Periodontol 2012;16:200-6
|How to cite this URL:|
Chadha VS, Bhat KM. The evaluation of doxycycline controlled release gel versus doxycycline controlled release implant in the management of periodontitis. J Indian Soc Periodontol [serial online] 2012 [cited 2021 Apr 12];16:200-6. Available from: https://www.jisponline.com/text.asp?2012/16/2/200/99262
| Introduction|| |
The earliest historical records dealing with human diseases and their treatment make a special mention of periodontal diseases and the need for treating them. The primary role of bacteria in the etiology of periodontal diseases is unequivocal. Treatments have been varied and numerous, yet traditional mechanical debridement to disrupt the subgingival flora and provide clean, smooth, and biologically compatible root surfaces is still the mainstay. In spite of the excellent results achieved, mechanical debridement alone has shown to leave behind a significant number of pathogenic microorganisms in relatively inaccessible areas.
A microbiological approach to periodontal therapy aims primarily at suppressing specific pathogenic bacteria and permitting a subsequent recolonization of a microbiota compatible with health.  The various methods used to deliver antimicrobial agents include rinsing, irrigation, systemic administration, and local application using sustained and controlled delivery devices.
Systemic delivery enables the antimicrobial agent to reach all periodontal and oral sites. However, it achieves relatively low drug levels within the periodontal pocket and poses a risk of adverse reactions to nonoral body sites. Medicaments have also been delivered via mouth rinses and supragingival irrigation, but the depth of penetration of the medicaments via these means into the periodontal pocket is limited. , Subgingival irrigation of antimicrobials has shown reasonably good results with high initial drug concentrations in pockets. However, drawbacks with irrigation systems are a small drug reservoir and exponential kinetics, which tend to shorten the period of effective drug concentration. In addition, oral irrigation may not facilitate the penetration of the drug to the deepest areas of the pocket and self-irrigation may be limited by poor patient compliance.
Local antimicrobial therapy in periodontitis involves direct placement of an antimicrobial agent into diseased subgingival sites, bypassing other oral and nonoral body sites. The concept of controlled release local delivery of therapeutic antimicrobial agents was championed and developed into a viable concept primarily by Dr. Max Goodson, whose first delivery device involved hollow fibers of cellulose acetate filled with tetracycline.  The initial reports using locally delivered tetracycline were promising, hence other antibiotics in several different types of vehicles were also investigated to develop sustained release delivery systems for periodontal treatment.
By means of controlled local delivery from within the periodontal pocket, a single administration of a small amount (milligrams) of the antibacterial agent required can maintain therapeutic concentrations within the gingival crevicular fluid for a longer period of time than any other mode of delivery. The antimicrobial agents used have been incorporated into gels, pastes, films, strips, polymers, and fibers as vehicles for local controlled drug release into the periodontal pockets. 
This study was done in an attempt to evaluate the benefits of the adjunctive use of doxycycline controlled release gel versus doxycycline controlled release implant in the management of periodontal pockets by estimating the drug concentration in the gingival crevicular fluid and saliva and also assessing their clinical effects over a period of 90 days.
| Aims and Objectives|| |
This study was designed to assess the efficacy of locally made doxycycline gel versus locally made doxycycline implant as biodegradable controlled local delivery systems, used as an adjunct to scaling and root planing by evaluating the following criteria:
- Pharmacological drug release: To assess the gingival crevicular fluid and salivary concentrations of the drug (doxycycline) released from the respective gel and implant systems at various intervals
- Clinical examination: To assess the improvement in gingival status, gain in attachment, and reduction in probing pocket depth.
| Materials and Methods|| |
Preparation of the biodegradable implants
Ingredients: Doxycycline hyclate 60 mg, carbopol 934P NF 180 mg, poly-∈-caprolactone 1.2 g, dichloromethane 8.0 ml.
Procedure: Poly-∈-caprolactone was dissolved in dichloromethane and carbopol 934P to form a polymer solution into which the drug was then dissolved. The dispersion was then sonicated to make it uniform throughout, poured in a glass mould lined with aluminium foil, and allowed to dry. The dried film was then cut into 0.5 cm Χ 0.5 cm films.
Preparation of the in situ gel
Ingredients: Doxycycline hyclate 25 mg, propylene glycol 0.25 g, poly(lactide-co-glycolide)/PLGA 0.50 g, triacetin 4.25 g.
Procedure: PLGA was placed in a glass vial, triacetin added, heated at 60° C, and agitated using a mechanical shaker overnight to obtain a clear solution. Doxycycline, dissolved in propylene glycol, was then added to the polymer solution and sonicated for 30 seconds to get a uniform dispersion. When PLGA solution comes into contact with the in vivo aqueous environment, it transforms to a solid matrix that releases the loaded drug for a prolonged period of time.
(Materials used in the preparation of both gel and implant are approved by the US FDA for biomedical applications and approved by the institution board for human trials.)
In vivo study
Thirty patients with localized periodontal pockets measuring ≥5 mm and without any systemic disorders were selected from among the patients visiting the Department of Periodontics, College of Dental Surgery, Manipal. Care was taken to see that the selected patients did not have a history of antibiotic therapy in the past 6 months. All patients participating in this study were informed of the details of the study and their consent was taken before starting the study.
Selected patients received a full mouth supragingival and subgingival scaling, root planing, and polishing. Oral hygiene instructions were given. Patients were then recalled after 2 weeks for reevaluation of the periodontal status. Patients who showed a reduction in pocket depth owing to gingival shrinkage were eliminated and only those 30 patients who had pocket depths ≥5 mm were selected for the final study. These 30 patients (14 males and 16 females) were then randomly divided into three groups, with 10 patients per group. The first group received the doxycycline gel, the second group the doxycycline implant, and the third group received only scaling and root planing (the control group). The patients in the first two groups were selected for the drug release profile (from the gel and implants, respectively).
The following parameters were recorded:
- Gingival index (Loe and Silness), 
- Plaque index (Silness and Loe) 
- Distance from crest of marginal gingival to cementoenamel junction (MG to CEJ)
- Distance from crest of marginal gingival to base of pocket (MG to BOP)
- Distance from cementoenamel junction to base of pocket (CEJ to BOP).
An occlusal stent with a groove was made to standardize probe placement in the pocket. All the measurements including MG to CEJ, MG to BOP, and CEJ to BOP were taken at baseline, that is, 2 weeks after scaling and root planing and before insertion of the gel [Figure 1] or implant [Figure 2] in the gel and implant groups respectively.
The area was dried properly with gauze and well isolated. The pocket wall was then separated from the tooth surface with the help of an air syringe; 0.2 ml of the gel was carefully injected into the periodontal pocket with help of a syringe and needle [Figure 3]. When the PLGA (poly lactide-co-glycolide) solution comes in contact with the in vivo aqueous environment, it transforms to a solid matrix that releases the loaded drug for a prolonged period of time.
The area was dried properly with gauze and well isolated. The pocket wall was then separated from the tooth surface with the help of an air syringe. The implant was then carefully inserted into the periodontal pocket with the help of a tweezer in such a way that the whole implant was submerged in the pocket [Figure 4]. Once the implant comes in contact with the gingival crevicular fluid, it swells up and adheres to the lateral wall of the pocket due to the mucoadhesive property of poly ∈-caprolactone and carbopol 934P.
Following mechanical instrumentation, no other treatment was done in the control group.
No attempt was made to supervise the patients' brushing techniques or reinforce the oral hygiene instructions previously given. The patients were advised to refrain from the use of mouthwashes, not to take any antibiotics, NSAIDs, or oral contraceptives during the course of the study. All the patients had good general health, did not smoke, and did not give a history of allergy to doxycycline/tetracycline group of antibiotics. Pregnant women or lactating mothers were not included in the study. Periodontal pockets in which the pocket depth corresponded to the tooth apex or teeth which were associated with periapical pathology were not included in the study.
All the measurements were repeated on the 90 th day following placement of the implant/gel [Figure 5] and [Figure 6], and changes in pocket depth and level of attachment were calculated.
The gingival crevicular fluid and saliva were collected 1 hour following gel/implant placement and then at every recall visit, i.e., on the 10 th , 30 th , and 60 th days after placement of the gel/implant. Whatman No. 1 filter paper discs of 6 mm diameter were used to collect the samples. The filter paper disc with the sample was transferred to a vial containing 5 ml of isotonic phosphate buffer saline. This solution was analyzed using the Hewlett Packard UV spectrophotometer to obtain absorbance of the drug in 1 ml of the solvent. The mean gingival crevicular fluid (GCF) and salivary concentrations of doxycycline were then calculated.
The collected data were analyzed using the statistical package, SPSS/version 7.0. The Mann-Whitney U test was used for comparison. A P value <0.05 was considered statistically significant.
| Results and Observations|| |
The release profile of doxycycline hyclate from the biodegradable gel and implant is shown in [Table 1]. The concentration of doxycycline in the GCF was found to be much higher than the salivary concentration. When the release profile of doxycycline from the gel and implant systems was compared, a statistically significant difference was found in the release of doxycycline from the gel when compared with the implant, in the GCF at the end of 1 hour (P<0.01) and on the 10 th and 30 th days (P<0.05). There was no statistically significant difference (P>0.05) between the two systems in the doxycycline concentration in the GCF on the 60 th day.
There was no statistically significant difference in the doxycycline concentrations in the saliva, released from the gel and implant systems at the end of 1 hour (P>0.05). There was, however, a statistically significant difference (P<0.05) in salivary doxycycline concentrations of the gel when compared with the implant on the 10 th and 30 th days. There was no significant difference (P>0.05) in the salivary drug concentrations of the two delivery systems on the 60 th day.
A comparison of the clinical parameters is given in [Table 2] and [Table 3].
|Table 2: Comparison of clinical parameters between baseline values and 90th day values|
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- Plaque score: All three groups showed a reduction in plaque scores. Both gel and implant groups showed a statistically significant reduction in plaque scores (P<0.01) when compared with the control group, but there was no statistically significant difference between the gel and implant groups (P>0.05).
- Gingival inflammation: All three groups showed a reduction in gingival inflammation. Both gel and implant groups showed a statistically significant reduction in gingival inflammation scores (P<0.001) when compared with the control group, but there was no statistically significant difference between the gel and implant groups (P>0.05).
- Probing depth: All three groups showed a reduction in probing depth from baseline to the 90 th day. When the groups were compared, the reduction in probing depth was statistically significant for both gel and implant groups when compared with the control group (P<0.01), but there was no statistically significant difference between the gel and implant groups (P>0.05) in the reduction achieved.
- Gain in attachment level: All three groups showed a gain in attachment from baseline to the 90 th day. On comparison of the three groups, it was found that the gain in attachment level was statistically significant for both gel and implant groups when compared with the control group (P<0.01), but there was no statistically significant difference between the gel and implant groups (P>0.05) in the attachment gain achieved.
| Discussion|| |
A number of local or targeted delivery systems have been developed for administering antimicrobial agents to the subgingival environment. Two different forms of biodegradable controlled release drug delivery systems-gels and implants-were evaluated in this study after placement in periodontal pockets. Doxycycline, a semisynthetic tetracycline, was chosen due to its known efficacy against putative periodontal pathogens and potential clinical efficacy in modulating clinical signs of periodontitis in humans (Polson et al)  and fewer side effects when compared with tetracycline.
In this study, the mean GCF concentration of doxycycline ranged from 5.8650 μg/μl 1 hour after gel placement to 2.4385 μg/μl at the end of 60 days, while that of the implant ranged from 3.2244 μg/μl 1 hour after implant insertion to 2.2990 μg/μl on the 60 th day. The mean salivary concentrations ranged from 0.8177 μg/μl at the end of 1 hour to 0.9143 μg/μl at the end of 60 days for the gel and from 0.7853 μg/μl at 1 hour to 0.6805 μg/μl at 60 days for the implant. The concentration of doxycycline released from the gel was significantly greater than from the implant in the GCF at 1 hour, 10 days, and 30 days and in the saliva at 10 days and 30 days. The initial higher drug release from the gel is attributed to the rapid release of drug from the fluid gel before its solidification within the periodontal pocket.  Stoller et al, reported that the release of doxycycline hyclate (from a biodegradable gel) in the GCF peaked 2 hours after placement with levels between 1473 μg/ml and 1986 μg/ml. The levels remained consistently above 1000 μg/ml till 18 th hour and then declined till the 7 th day. In this study, the GCF and salivary doxycycline concentrations were well above the required minimum inhibitory concentration (MIC) (0.1-2.0 μg/ml)  even on the 60 th day, to have an antibacterial effect.
Both gel and implant groups showed statistically significant reductions in plaque scores, gingival inflammation, and probing depth and gain in attachment levels from baseline to the 90 th day. The control group also showed improvement in all clinical parameters; however, only reduction in probing depth and gain in attachment level were clinically significant. Polson et al, reported doxycycline hyclate delivered in a biodegradable delivery system to be an effective means of reducing the clinical signs of adult periodontitis. Garrett et al, Wennstrom et al,  and Eickholz et al, in separate studies, compared the clinical results obtained following only scaling and root planing with locally delivered doxycycline. They concluded that subgingival doxycycline is a useful adjunct to conventional mechanical therapy in the nonsurgical management of chronic periodontitis.
Both the gel and implant were found to be useful drug delivery systems in the treatment of localized periodontitis. No difference was found between the gel and implant systems as far as improvement in clinical parameters was concerned. The possible advantage of a gel is its syringeability and therefore ease of placement (Needleman).  Being more fluid, the gel is able to adjust to the shape and size of the pocket.  A gel, however, is limited by rapid drug release as the drug is more free to diffuse out (Needleman).  In this study, drug concentrations were maintained above the MIC for the entire 60 days in the gel group in spite of an initial rapid drug release. The implant on the other hand is rigid and comes in a standard size. To ensure that 1 mg of drug is delivered to the diseased site, the entire implant has to be placed within the periodontal pocket. A gel may be easily placed in tortuous or narrow pockets or relatively inaccessible areas as it can be directly syringed into these areas, whereupon it will solidify and release the drug. Implants owing to their rigidity may be required to be placed in larger or compound pockets.
| Conclusion|| |
The following conclusions may be drawn from the study:
- Mechanical nonsurgical therapy of scaling and root planing results in significant changes in pocket depth
- Additional use of local delivery of doxycycline through gel and implant media further enhances the positive changes obtained following scaling and root planing
- The release of doxycycline from the implant and gel was comparable, both releasing the drug above the required MIC
- Doxycycline delivered locally may be used in the management of chronic periodontitis.
| Acknowledgment|| |
The authors like to thank Dr. G. Subraya Bhat (Prof. Department of Periodontics, CODS, Manipal), Dr. Sunil Aggarwal PhD, Dr. Venkatesh PhD, and Dr. Udupa (Prof. and Head, College of Pharmaceutical Sciences, Manipal).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]