Journal of Indian Society of Periodontology
Journal of Indian Society of Periodontology
Home | About JISP | Search | Accepted articles | Online Early | Current Issue | Archives | Instructions | SubmissionSubscribeLogin 
Users Online: 130  Home Print this page Email this page Small font size Default font size Increase font sizeWide layoutNarrow layoutFull screen layout

   Table of Contents    
ORIGINAL ARTICLE
Year : 2022  |  Volume : 26  |  Issue : 4  |  Page : 378-383  

A new era of Nano!!! Comparative evaluation of ganglioside polymeric nanoparticle coated satranidazole gel and 1% metronidazole gel for the treatment of periodontitis


1 Division of Periodontology, Faculty of Dental Science, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Submission09-Apr-2021
Date of Decision01-Dec-2021
Date of Acceptance10-Jan-2022
Date of Web Publication02-Jul-2022

Correspondence Address:
Sarita Parihar
Division of Periodontology, Faculty of Dental Science, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisp.jisp_233_21

Rights and Permissions
   Abstract 


Background: The present study was intended to comparatively assess the efficacy of ganglioside polymeric nanoparticle-coated 0.25% satranidazole-loaded nanoparticles in gel form with that of the commercially available 1% metronidazole gel as a local drug delivery (LDD) agent for the treatment of periodontal pockets. Materials and Methods: A split-mouth randomized clinical trial was carried out in 46 chronic periodontitis patients with probing pocket depth (PPD) ≥4 mm or clinical attachment loss greater than 3 mm on both quadrants of the same arch. Full-mouth scaling and root planing (SRP) was performed for all the patients followed by application of 0.25% satranidazole-loaded nanoparticles in gel form on one site (Group 1) and commercially available 1% metronidazole gel on another site (Group 2). Clinical parameters (gingival index, plaque index, PPD, clinical attachment level gain, and bleeding on probing) and microbiological analysis of the subgingival plaque samples were performed and assessed at baseline, after SRP, 21st day, and 90th day post treatment. Unpaired “t”-test and ANOVA tests were used for intergroup and intragroup comparison of recorded parameters. Results: The results showed that the satranidazole-loaded nanoparticle group as an adjunct to SRP in chronic periodontitis showed a statistically significant improvement in all the clinical parameters and a fewer relapse of microbial flora in comparison with the metronidazole group as an LDD agent. Conclusion: The present study depicted that both the LDD agents showed an effective improvement of clinical as well as microbiological parameters, but the satranidazole group consistently produced better results than the metronidazole group and hence has a promising future as an LDD agent in treating periodontal pockets.

Keywords: Chronic periodontitis, local drug delivery, metronidazole, nanoparticles, satranidazole


How to cite this article:
Kesarwani S, Parihar S, Singh S, Gautam A, Pandey A, Anjum MM. A new era of Nano!!! Comparative evaluation of ganglioside polymeric nanoparticle coated satranidazole gel and 1% metronidazole gel for the treatment of periodontitis. J Indian Soc Periodontol 2022;26:378-83

How to cite this URL:
Kesarwani S, Parihar S, Singh S, Gautam A, Pandey A, Anjum MM. A new era of Nano!!! Comparative evaluation of ganglioside polymeric nanoparticle coated satranidazole gel and 1% metronidazole gel for the treatment of periodontitis. J Indian Soc Periodontol [serial online] 2022 [cited 2022 Aug 18];26:378-83. Available from: https://www.jisponline.com/text.asp?2022/26/4/378/349727




   Introduction Top


Although chronic periodontitis is the most prevailing manifestation of periodontitis and demonstrates features of a slowly progressing inflammatory disease, the genetic makeup, systemic comorbidities, and various environmental factors might alter the host's immune response to the dental biofilm subsequently making periodontal destruction more progressive.[1] The chief treatment modality for chronic periodontitis is thorough oral hygiene maintenance by scaling and root planing (SRP) done conventionally either by the use of hand scalers and curettes or ultrasonic devices. However, complete mechanical debridement becomes a challenge for the clinician in sites with deep periodontal pockets and root surface complexities and requires adjunctive treatment modalities in combination with the conventional therapy which include systemic antimicrobial agents, local drug delivery (LDD), open access debridement, or the application of lasers for the eradication of pockets and residual calculus.[2]

A more strategic treatment of sustained release drug delivery systems to deliver the therapeutic factors in a controlled fashion over a designated period of time directly into the gingival crevices is preferred as they not only eliminate systemic uptake of drug but also reduce bacterial resistance.[1] However, there exists a risk of dislodgement of the LDD agents from the pocket. To combat this limitation, a self-adhesive gel that is easy to apply, stays for a longer period of time, and provides optimum results, is required.

Metronidazole- and nitroimidazole-related derivatives have been very popular as local site-specific drugs for the treatment of chronic periodontitis, but this drug requires frequent applications and leaves a bitter metallic taste, which adversely affects its use.[3],[4]

Satranidazole is a novel nitroimidazole with 2° of the imidazole ring connected via nitrogen to a substituted imidazolidinone moiety. It serves as an alternative to metronidazole with less nauseating influence, milder taste, and four-fold more potency against Gram-negative bacteria.[5],[6] These positive properties led to the evolution of interest in the use of satranidazole in treating Gram-negative anaerobic bacterial infections, especially in the oral cavity. Singh et al.[7] developed a ganglioside polymeric nanoparticles (G-PNP)-coated formulation of satranidazole with great success.

Thus, this study was designed to assess the efficacy of G-PNP-coated 0.25% satranidazole gel in treating chronic periodontitis and to clinically compare results with that of the commercially available 1% metronidazole gel.


   Materials and Methods Top


The present study was concurred by the institutional ethical board, and written informed consent was procured from all the selected patients.

The study included patients clinically diagnosed as localized/generalized mild-to-moderate chronic periodontitis (AAP 1999 classification) and with probing pocket depth (PPD) ≥4 mm or clinical attachment loss >3 mm on both quadrants of the same arch with no periodontal treatment carried out in the last 6 months. All third molars, patients with active endodontic-periodontal lesions, using tobacco or related products, chronic smokers, alcoholics, history of previous antibiotic therapy within the past 3 months, with known allergy to metronidazole and related groups, immunocompromised, pregnant woman, and lactating mothers were excluded.

Materials used were 0.25% satranidazole gel and 1% w/w metronidazole gel.

Nanoprecipitation method which was developed by Fessi et al.[8] was employed for preparation of G-PNP. In a bath sonicator, SZ (30 mg) and PCL (180 mg) were dissolved in 5-ml acetone at room temperature. Separately, 125 mg of poloxamer 188 was dispersed in 20-ml water [Figure 1]. The organic phase was carefully loaded in a 23-gauge syringe and injected at a rate of 10 ml/min into the aqueous phase continuously being stirred at 800 rpm. The milky nanosuspension (NS) formed was then stirred continuously for 2 h at the same speed and was concentrated by removal of acetone and excess water via a rotatory evaporator (IKA). The resulting suspension was then monitored for particle size and entrapment efficiency to obtain the best formulation. The mean particle size and polydispersity index of formulations were determined using a particle size analyzer and Delsa Nano C (Beckman Coulter, USA) functioning on dynamic scattering technique. The samples were later diluted with water in a ratio of 1:20 to obtain ideal 50–200 kilo counts per second measurements. A method employed by Jain et al.[9] was used for determination of entrapment efficiency. The method of Varshosaz et al.[10] was followed to prepare the gel. Weighed CB 934P was dispersed in 25-ml water. NS was added to CB934P dispersion, concomitantly introducing gelling agent (SCMC, HPC, HEC, and HPMC) slowly under manual stirring. Gels were left overnight to afford solubilization of the excipients, forming a visibly uniform structure. The concentration of SZ (0.25% w/v) was kept constant in all batches.
Figure 1: Flowchart depicting preparation of satranidazole gel. PCL – polycaprolactone

Click here to view


A total of 50 subjects of chronic periodontitis in coherence with the inclusion and exclusion criteria were considered. Four patients did not turn up for follow-up, thus 46 patients were included in the study. A pilot study was done on 4 patients to obtain total number of subjects. The study sites were randomly categorized into two groups as follows:

Group I: satranidazole gel (0.25%) used as an LDD agent and Group II: metronidazole gel (1%) used as an LDD agent. Opposite arch acted as a positive control group.

PPD and clinical attachment level (CAL) were recorded at six sites around each tooth using the stent that helped to reproduce unbiased measurements during the 21st and 90th days post treatment. Gingival index (GI),[11] plaque index (PI),[12] and bleeding on probing were recorded.[13] All the parameters were recorded by UNC 15 periodontal probe (UNC Periodontal Probe, Hu-Friedy, Chicago, IL, USA) [Figure 2] and [Figure 3].
Figure 2: Baseline probing pocket depth recording in Group 1

Click here to view
Figure 3: Baseline probing pocket depth recording in Group 2

Click here to view


Subgingival plaque samples were collected with the help of sterile paper points and transported to the laboratory for conventional polymerase chain reaction assay. It was used to identify the presence of anaerobic bacteria such as Porphyromonas, Fusobacterium, Tannerella, and Bacteroides at baseline 21st day and 90th day post treatment.

All the patients underwent full-mouth SRP followed by intervention by the same operator. In one patient, the groups (satranidazole and metronidazole) were divided cohering with the treatment received in opposite quadrants of the same arch. All the experimental sites were treated once daily in Group A and twice in Group B. The gels were administered to the bottom of the periodontal pocket by using a disposable syringe equipped with round needle of 23 gauze [Figure 4] and [Figure 5]. The gels were injected into the pockets until the gel overflowed from the gingival margin. The pocket was sealed with periodontal dressing following therapy. Patients were advised to brush by Charter method after removal of periodontal dressing and refrain from mouthwash or any other drug during entire study duration. The sites were reassessed for clinical and microbiological parameters at the 21st and 90th days post treatment [Figure 6] and [Figure 7].
Figure 4: Local drug delivery with satranidazole drug

Click here to view
Figure 5: Local drug delivery with metronidazole drug

Click here to view
Figure 6: Post treatment probing pocket depth recording in Group 1

Click here to view
Figure 7: Post treatment probing pocket depth recording in Group 2

Click here to view


The statistical analysis was done using SPSS 16 (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc.). Mann–Whitney test was done for comparing bleeding on probing. For PI, GI, and PPD, unpaired “t”-test was done to compare between the groups and ANOVA test was done to compare within the group. For CAL gain, unpaired “t”-test was done to compare between the groups and paired “t”-test was done to compare within the group.


   Results Top


[Table 1] depicts a statistically highly significant reduction in GI, PI, and PPD with P < 0.000 in all the parameters in all the groups.
Table 1: Intragroup assessment of improvements in periodontal parameters from baseline, 21st day, and 90th day post intervention in subjects of Group 1 and Group 2

Click here to view


[Table 2] shows a statistically highly significant gain in CAL with P < 0.000 in all the groups.
Table 2: Intergroup assessment of improvement in clinical attachment level gain from baseline to 21st day and 90th day post intervention in subjects of Group 1 and Group

Click here to view


[Table 3] shows a significant reduction of bleeding on probing in both the groups. Furthermore, considerably more reduction in bleeding on probing was seen in Group 1 than Group 2.
Table 3: Intergroup assessment of bleeding on probing in subjects of Group 1 and Group 2 at baseline, 21st day, and 90th day post intervention

Click here to view


[Table 4] shows that except GI and PI from 21st day to 90th day postintervention, all other parameters showed reduction of values. However, difference was statistically not significant in PI at baseline, 21st day, and 90th day post treatment. PPD and GI at baseline between the groups were statistically not significant.
Table 4: Intergroup comparison in periodontal parameters in subjects of Group 1 and Group 2 at baseline, 21st day, and 90th day post intervention

Click here to view


[Table 5] shows a reduction in counts of Porphyromonas, Fusobacterium, Prevotella, and Bacteroides in both the groups. However, more reduction of Prevotella and Bacteroides was seen in Group 1 subjects.
Table 5: Assessment of Porphyromonas, Fusobacterium, Prevotella, and Bacteroides in subjects of Group 1 and Group 2 at baseline, 21st day, and 90th day post intervention

Click here to view



   Discussion Top


It has been well proven that in chronic periodontitis patients, SRP along with adjuvant antibiotics gives better results when compared with SRP alone.[14] However, conventional SRP may fail to abolish the putative subgingival periodontal microflora located in difficult areas such as multirooted teeth, furcation sites, concavities, interproximal areas, and deep pockets inaccessible to periodontal instruments.[15],[16] However, even after complete SRP, bacteria might persist in root cementum and dentinal tubules, and may migrate from these reservoirs to periodontal areas.[17] Therefore, for periodontal therapy, anti-infective agents such as local or topical or systemic antibiotics may be used as an adjunctive measure.[18] LDD has the ability to deliver the antibiotic to the target sites, achieve higher concentration, last for sufficient duration to be effective as it possesses high patient acceptability.[17] The present study was conducted to analyze the effects of adjunctive administration of satranidazole and metronidazole gels during SRP in cases of moderate-to-severe chronic periodontitis on the basis of clinical and microbiological results. The test hypothesis accepted was that both satranidazole and metronidazole gels can be used as adjuvant therapy for the management of chronic periodontitis.

Change of mean PPD and GI and CAL gain at 90 days was set as the important clinical outcome. Clinically, all periodontal parameters consistently showed a change toward the better except PI. In our study, we found a reduction of 35% in the probing depth as compared to the baseline by the use of satranidazole gel. Singh et al.[7] described a decrease in probing depth of about 23% compared to baseline by using the same formulation. The promising results of satranidazole lead us toward better supportive periodontal therapy with minimum efforts and investments which can be easily carried in dental setup. No side effects, as may be observed with oral administration, were noticed.

The advantage with the use of satranidazole mucoadhesive gel is the short course of treatment, along with only one daily local application which facilitates patient compliance as compared to metronidazole gel. The gangliosidic coating of polymeric nanoparticles (G-PNP) on the satranidazole particles interacts with gingival immunologic representatives to assert a Th2 dominant cytokine pattern, which in turn could have accelerated disease remission. The findings of this study are in agreement with that of Crespo et al.[19] who also stated that these GNP-coated particles are better suited for LDD than simply polymeric mucoadhesive particles or nanoparticles. Singh et al.[7] had hypothesized that the delivery of satranidazole in the form of PNP will tackle the inherent aqueous dispersibility issue of satranidazole along with providing a biphasic drug release effective in tackling periodontal bacteria. Bansal et al.[20] used various types of drug formulations for LDD of SZ in periodontitis patients. According to them, employment of 3% w/v satranidazole gel has the optimal balance of mechanical properties (mucoadhesiveness, hardness, adhesiveness, compressibility, and cohesiveness) to be used in subgingival conditions. This formulation was also used by Priyanka et al.[21] who also reported a constant and prolonged concentration at the application site, thus providing better and stable results. Highly statistically significant changes were also observed for GI and PI. After 90 days, a reduction in bleeding on probing (BOP) of 52% was seen in the sites treated with satranidazole. These results are in sync with those reported by Priyanka et al.[21] where they reported a PPD reduction in the subjects treated with satranidazole along with SRP. The results of this study are also supported by Bansal et al.[20] who reported a percentage reduction of 68%, 73%, 52%, 58%, and 74% in PD, PI, GI, CAL, and BI (bleeding index) from the baseline, respectively, in patients treated with satranidazole gel. In the current study, a PPD reduction observed with the adjuvant usage of metronidazole gel was statistically highly significant (P = 0.000). Similar changes were observed for the gingival index and PI where the results were statistically highly significant (P = 0.000) for both. Ciurba et al.[22] demonstrated that PI, BOP, and PPD at 1 month post treatment had better values in comparison with those of the initial examination values in a greater number of the periodontal examined sites (PI – 54.15%, BOP – 62.38%, and PPD – 28.45%) in the patients receiving SRP and 15% metronidazole gel formulation. Thus, the present study reiterates the efficacy of metronidazole gel as an adjunctive therapeutic modality for the treatment of chronic periodontitis. Comparing both the drugs employed here, better result was given by satranidazole for all parameters and for all time spans except PI.

In the metronidazole group, 70% bleeding on probing was noticed showing relapse after 90 days signifying a return to the initial conditions, whereas satranidazole showed a relapse tendency of only 48% [Table 3]. This difference between the two drugs was highly statistically significant (P = 0.000). This study gains further validation from the study of Miani et al.[23] who reported an increase in bacterial population after initial reduction in bacterial load measured at 7 days and 30 days post metronidazole treatment. Most of the studies conducted earlier have compared drugs with placebo or SRP alone. To the best of our knowledge, no study has been conducted till date to assess the clinical efficacy of satranidazole gel in comparison with metronidazole gel.

An important criterion stated by Socransky[24] for a specific bacterium to be inferred as pathogen, is that it must be present in high numbers at diseased sites and absent in healthy sites. Specific periodontal pathogens, for instance, such as Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Fusobacterium, have been considered to be causative agents for chronic periodontitis. In this study, a return of Porphyromonas and Fusobacterium species was seen after 90 days of the study in the satranidazole group [Table 5]. The metronidazole group, however, showed the presence of bacteria even after 21 days of constantly giving the drug. The study was primarily conducted to check the presence or absence of Gram-negative anaerobes which are primarily indicated in the oral infections and pathologies. A total absence of microbes from the satranidazole group at 21 days is a promising indication. Moreover, when compared to the metronidazole group, the results of satranidazole are far better. The presence of Porphyromonas and Fusobacterium in our study even after antibiotic therapy once again proves the complex nature of the oral bacterial biofilm.


   Conclusion Top


The results of this study showed that both drugs produced beneficial results in combination with SRP for treating chronic periodontitis, but satranidazole gel consistently produced better results compared to metronidazole gel. However, since this was a short-term study where the subjects were followed for only 90 days, future studies should be conducted in a randomized multicenter trial with larger sample size and long-term follow-up for further validation.

Acknowledgement

We would like to thank P G Naveen Kumar, Department of Community Dentistry, Banaras Hindu University, Varanasi 221005.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 2005;366:1809-20.  Back to cited text no. 1
    
2.
Newman M, Takei H, Klokkevold P, Carranza F. Clinical Periodontology. 12th ed. Philadelphia, PA: W.B. Saunders; 2013.  Back to cited text no. 2
    
3.
Prakasam A, Elavarasu SS, Natarajan RK. Antibiotics in the management of aggressive periodontitis. J Pharm Bioallied Sci 2012;4:S252-5.  Back to cited text no. 3
    
4.
Brunton L, Lazo J, Parker K. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York: Mcgraw Hill; 2005.  Back to cited text no. 4
    
5.
Muzaffar J, Madan K, Sharma MP, Kar P. Randomized, single-blind, placebo-controlled multicenter trial to compare the efficacy and safety of metronidazole and satranidazole in patients with amebic liver abscess. Dig Dis Sci 2006;51:2270-3.  Back to cited text no. 5
    
6.
Gowrishankar R, Phadke RP, Oza SD, Talwalker S. Satranidazole: Experimental evaluation of activity against anaerobic bacteria in vitro and in animal models of anaerobic infection. J Antimicrob Chemother 1985;15:463-70.  Back to cited text no. 6
    
7.
Singh Y, Vuddanda PR, Jain A, Parihar S, Chaturvedi TP, Singh S. Mucoadhesive gel containing immunotherapeutic nanoparticulate satranidazole for treatment of periodontitis: Development and its clinical implications. RSC Adv 2015;5:47659-70.  Back to cited text no. 7
    
8.
Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 1989;55:R1-4.  Back to cited text no. 8
    
9.
Jain A, Singh SK, Singh Y, Singh S. Development of lipid nanoparticles of diacerein, an antiosteoarthritic drug for enhancement in bioavailability and reduction in its side effects. J Biomed Nanotechnol 2013;9:891-900.  Back to cited text no. 9
    
10.
Varshosaz J, Tavakoli N, Saidian S. Development and physical characterization of a periodontal bioadhesive gel of metronidazole. Drug Deliv 2002;9:127-33.  Back to cited text no. 10
    
11.
Loe H, Silness J. Periodontal disease in pregnancy. I. Prevalence and severity. Acta Odontol Scand 1963;21:533-51.  Back to cited text no. 11
    
12.
Silness J, Loe H. Periodontl disease in pregnancy. II. Correlation between oral hygience and periodontal condition. Acta Odontol Scand 1964;22:121-35.  Back to cited text no. 12
    
13.
Newbrun E. Indices to measure gingival bleeding. J Periodontol 1996;67:555-61.  Back to cited text no. 13
    
14.
Fleming TF. Periodontitis. Ann Periodontol 1999;4:32-8.  Back to cited text no. 14
    
15.
Oda S, Nitta H, Setoguchi T, Izumi Y, Ishikawa I. Current concepts and advances in manual and power-driven instrumentation. Periodontol 2000 2004;36:45-58.  Back to cited text no. 15
    
16.
Obeid PR, D'Hoore W, Bercy P. Comparative clinical responses related to the use of various periodontal instrumentation. J Clin Periodontol 2004;31:193-9.  Back to cited text no. 16
    
17.
Umeda M, Takeuchi Y, Noguchi K, Huang Y, Koshy G, Ishikawa I. Effects of nonsurgical periodontal therapy on the microbiota. Periodontol 2000 2004;36:98-120.  Back to cited text no. 17
    
18.
Drisko CH. Non-surgical pocket therapy: Pharmacotherapeutics. Ann Periodontol 1996;1:491-566.  Back to cited text no. 18
    
19.
Crespo FA, Sun X, Cripps JG, Botran RF. The immunoregulatory effects of gangliosides involve immune deviation favoring type-2 T cell responses. J Leukoc Biol 2006;79:586-95.  Back to cited text no. 19
    
20.
Bansal K, Rawat MK, Jain A, Rajput A, Chaturvedi TP, Singh S. Development of satranidazole mucoadhesive gel for the treatment of periodontitis. AAPS PharmSciTech 2009;10:716-23.  Back to cited text no. 20
    
21.
Priyanka N, Kalra N, Saquib S, Kudyar N, Malgaonkar N, Jain H, et al. Clinical and microbiological efficacy of 3% satranidazole gel as a local drug delivery system in the treatment of chronic periodontitis: A randomized, controlled clinical trial. Contemp Clin Dent 2015;6:364-70.  Back to cited text no. 21
[PUBMED]  [Full text]  
22.
Ciurba A, Lazar L, Antonoaea P, Georgescu AM, Vari CE, Todoran N. In vitro/in vivo performance study of new metronidazole periodontal gel formulations. Farmacia 2015;63:11-9.  Back to cited text no. 22
    
23.
Miani PK, do Nascimento C, Sato S, Filho AV, da Fonseca MJ, Pedrazzi V. In vivo evaluation of a metronidazole-containing gel for the adjuvant treatment of chronic periodontitis: Preliminary results. Eur J Clin Microbiol Infect Dis 2012;31:1611-8.  Back to cited text no. 23
    
24.
Socransky SS. Relationship of bacteria to the etiology of periodontal disease. J Dent Res 1970; 49:203-222.  Back to cited text no. 24
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
   
 
  Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
    Materials and Me...
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed260    
    Printed12    
    Emailed0    
    PDF Downloaded98    
    Comments [Add]    

Recommend this journal