Dr Jagjit Singh - Jpmcp · The primary role of bacteria in the etiology of periodontal diseases is unequivocal. Despite of various treatment modalities, yet traditional mechanical

Singh J, Singh R, Gambhir RS, Shewale A, Mahajan R. Local Drug Delivery System In Treatement of

Periodontitis: A Review. J Periodontal Med Clin Prac 2016;03: 153-160

1 2 3 4* 4Dr Jagjit Singh , Dr Rina Singh ,Dr Ramandeep Singh Gambhir ,Dr Akhilesh Shewale ,Dr Rupali Mahajan

Local Drug Delivery System in Treatment of Periodontitis: A Review

Review Article

Affiliation

1. Dept. of Periodontology, BRS Dental College and Hospital, Panchkula.

2. Dept. of Prosthodontics, Gian Sagar Dental College and Hospital, Rajpura 3. Dept. of Public Health Dentistry, Gian Sagar Dental College and Hospital, Rajpura

4. Dept. of Periodontology, SDKSD College & Hospital , Nagpur 5. Periodontist , Private Practioner , Panchkula

Corresponding Author: Dr Jagjit Singh, Professor and Head, Dept. of Periodontology, BRS Dental College

and Hospital, Panchkula. Email- [email protected].

153

INTRODUCTION

The primary role of bacteria in the etiology of

periodontal diseases is unequivocal. Despite of

various treatment modalities, yet traditional

mechanical debridement to disrupt the subgingival

flora and provide clean, smooth, and biologically

compatible root surfaces is still the mainstay. Inspite

of this, mechanical debridement alone has shown to

leave behind a significant number of pathogenic

microorganisms in relatively inaccessible areas.

Elimination of putative periodontopathic

microorganisms in the subgingival microbiota is

essential for periodontal healing.

Systemically applied antimicrobials have been

advocated for the treatment of severe forms of

periodontitis. Early approaches to systemic

antibiotics in periodontal therapy included mainly

single drug therapies with Tetracycline, Penicillin, 1 Metronidazole or Clindamycin. However, it

achieves relatively low drug levels within the

periodontal pocket and poses a risk of adverse

reactions to non-oral 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 2,3the periodontal pocket is limited.

The local delivery of antimicrobial therapy to

periodontal pockets has the benefit of administering

more drugs at the target site while minimizing the

exposure of total body to the drug and the sustained 4 release of antimicrobial in the periodontal pockets.

Sustained local delivery systems might also be

recommended for sites considered as difficult to

instrument because of depth or anatomical

complexity, for example in the case of furcation 5defects.

LOCAL DRUG DELIVERY

The concept of controlled drug delivery in the

treatment of periodontitis was first proposed by

Goodson et al in 1979. The effectiveness of this

form of therapy is that it reaches the base of the

periodontal pocket and adequate time is available

for the drug to show its antimicrobial effect.

It has been observed that the local route of drug

delivery can attain 100-fold higher concentrations

of an antimicrobial agent in subgingival sites

Vol-III, Issue - III, Sep-Dec 2016

Local Drug Delivery System in Treatement of Periodontitis: A Review

compared with a systemic drug regimen. This

reduces the total patient dose by over 400 fold

thereby reducing the potential problems with the use

of systemic antibiotic drug regimens and

development of drug-resistant microbial 6populations at non oral body sites.

There are distinct phases of treatment plan where

dentist can use local antimicrobial therapy

1. As an adjunct to scaling and root planning.

2. Recurrent periodontitis sites that ideal for

treatment with this device.

3. Those who refuse surgical treatment or

medically compromised patients where

surgery is not an indication.

Various antimicrobial devices are used for the

purpose of treating periodontal diseases these

devices may be sustained release (drug delivered for

less than 24 hrs) or controlled release (drug 7delivered for more than 24 hrs).

CURRENTLY AVAILABLE LOCALLY

DELIVERED ANTIMICROBIALS IN

PERIODONTAL THERAPY

Tetracycline: They are the group of closely related

bacteriostatic antimicrobial and frequently used in

the treatment of refractory periodontitis, including 7localised aggressive periodontitis.

They are available in two forms of fibres and gel.

The Actisite tetracycline fibres have been approved

both by the United States Food and Drug

Administration (FDA) and by the European Union's

regulatory agencies. These are non-resorbable, safe,

inert copolymer loaded with 25% w/w tetracycline

HCI. It maintains constant concentration more than 81000 μg/mL for a period of 10 days. Following their

application a definite reduction in the subgingival 9 microbiota has been observed. Newman et al in

1994 did a 6 month multicentre evaluation of

adjunctive tetracycline fiber therapy and showed

that the fiber therapy significantly enhanced the

effectiveness of scaling and root planning in the

management of localised recurrent periodontitis

sites, in patients receiving regular supportive 10periodontal therapy.

Recently bioresorbable tetracycline fiber has been developed with base of collagen film, which is

commercially available as PERIODONTAL PLUS AB. It offers the advantage of no second

appointment for removal as it biodegrades within 7

days.

Tetracycline seratiopeptidase containing gels were

evaluated in a study by Maheshwari et al 2005. This

combination containing thermoreversible gel was

clinically effective along with scaling and root 11planing.

Doxycycline: It is a bacteriostatic agent having

anticollagenase activity by inhibiting the action of

MMP's that are capable of degrading extracellular 12matrix molecules including collagens.

Atridox is a FDA approved 10% doxycycline in a

gel system using a syringe. It is a subgingival

controlled released product composed of two 2

syringe mixing system. GCF levels reached its peak

to 1,500-2,000 in 2 hours following treatment with

Atridox. These levels remained above 1000 μg/mL

through 18 hours, and then levels gradually 13 declined. Levelof doxycycline are found to be well

maintained above the minimum inhibitory

concentration for periodontal bacteria (6.0 μg/mL) 14 through Day 7. Walker et al in 2000 in an attempt to

determine the effectiveness of sustained-release,

biodegradable gel containing 8.5% doxycycline on

the anaerobic flora and on antibiotic susceptibility

patterns associated with subgingival plaque and

saliva. They reported significant reduction in the


154

anaerobic bacteria but did not result in change in the 15

antibiotic resistant.

Minocycline: Locally delivered minocycline is a

bacteriostatic antibiotic and clinically available in

three modes i.e films, microsphere, ointment.

Film: they are available in the form of ethyl cellulose

films containing 30% of minocycline as sustained

release devices. Pragti S et al in 2009 showed that

insertion of this device subgingivally caused

complete eradication of periodontal pathogens in 14 16

days.

Microsphere: The FDA recently approved a new,

locally delivered, and sustained release form of

minocycline microspheres (ARESTIN) for

subgingival placement. The 2% minocycline is

encapsulated into bioresorbable microspheres (20-

60μm in diameter) in a gel carrier and has resorption

time of 21 days. Gingival crevicular fluid

hydrolyses the polymer and releases minocycline

for a period of 14 days or longer before resorbing 16

completely.

Ointment : Minocycl ine o in tment i s a

bioabsorbable sustained delivery system consisting

of 2% minocycline hydrochloride in a matrix of

hydroxyethyl-cellulose, aminoalkyl-methacrylate,

triacetine and glycerine. Dentomycin (2%

Minocycline gel) has received regulatory approval

for the treatment of periodontitis in the European

Union. The same product is available in Japan with

the name Periocline. The concentration of

minocycline in the periodontal pocket is about

1300μg/ml, 1 hr after single topical application of

0.05 ml ointment (1mg of minocycline) and is 17

reduced to 90μg/ml after 7 hrs.

Metronidazole: among the other antibiotics for

periodontitis metronidazole is preferred because of

its efficacy against obligate anaerobes. It is mostly

effective against subgingival anaerobic rods and

spirochetes. It is available as 25% Elyzol dental gel.

Elyzol contain oil based 25% metronidazole

(glyceryl mono-oleate and sesame oil). Greenstein

G et al suggested that there were better results with

the use of Elyzol over a 9-month observation period

when combined therapy was employed for probing 18

depth reduction.

Chlorhexidine: The use of chlorhexidine as an

antifungal and antibacterial agent has been well

established. The major application has been for the

control of dental plaque and gingivitis. Its

mechanism of action relates to reduction in pellicle

formation, alteration of bacterial adherence to teeth

and an alteration of bacterial cell walls causing lysis.

Because chlorhexidine is highly cationic, it exhibits

high substantivity. It is available in the form of

mouthrinses, Gels, varnishes and chips to be used as

local drug delivery.

Periochip: It is available as 2.5 mg of chlorhexidine

gluconate in a biodegradable matrix of hydrolysed

gelatin. It is a small orange- brown tomb shaped chip

of size (4.0x 0.5x 0.35mm)

Studies with PerioChip showed reduction in the

numbers of the putative periodontopathic organisms

Porphyromonas gingivalis, Prevotella intermedia,

Bacteroides forsythus and Campylobacter rectus

after placement of the chip. PerioChip releases

chlorhexidine in vitro in a biphasic manner, initially

releasing approximately 40% of the chlorhexidine

within the first 24 hours, and then releasing the

remaining chlorhexidine in an almost linear fashion

for 7–10 days. Study by Soskolne W.A in 1999

showed that there was an initial peak concentration



155

of chlorhexidine in gingival crevicular fluid at 2

hour after the chip was introduced. Slightly lower

concentrations being maintained over next 96 hrs.

Total degradation occurred between 7-10 days after 19

insertion.

Periocol –CG: It is prepared by incorporating

2.5mg chlorhexidine from a 20% chlorhexidine

solution in collagen membrane. Size of the chip is

4x5 mm and thickness is 0.25 - 0.32 mm and 10 mg

wt. Collagen is a natural protein, which is

chemotactic for fibroblasts, enhances fibroblast

attachment via its scaffold like fibrillar structure and

stimulates platelet degranulation, thereby

accelerating fibers and clot attachment. It has been

shown to resorb after 30 days; however their coronal 20

edge degrades within 10 days.

Hyaluronic acid (Gingigel®): available in forms of

m e m b r a n e , g e l s , s p o n g e s . I t i s a

mucopolysaccharide found in all living organisms

and is a main component of extracellular matrix.

Studies have shown hyaluronic acid to be anti-

inflammatory, anti-edematous, anti-oxidative and

anti-bacterial leading to their wide scope in the 21

treatment of periodontitis. 22

(Bansal J et al in 2010) showed the role of

hyaluronic acid in the periodontitis as

1. Antimicrobial agent as an adjunct to scaling

and root planning.

2. Bone regeneration in periodontal bony

defects.

3. Non- surgical treatment of peri-implant

pockets.

4. As an autologous cell hyaluronic acid graft

in mucogingival surgeries.

5. As a carrier for PDGF (platelet derived

g rowth f ac to r ) and BMP-2(bone

morphogenic protein) in regenerative

therapies.23

(Pirnazar P et al in 1999) showed bacteriostatic

effect of hyaluronic acid causing reduction in the

bacterial burden at the wound site, and improving

the clinical outcome of regenerative therapy. It is

found to be particularly effective against

Aggregatibacter actinomycetemcomitans,

Provetella oris, and Staphylococcus aureus stains

found in the periodontal wounds.

COENZYME Q (Perio Q®): It is a compound 10

naturally found in mitochondria and plays an

important role in electron transport chain process. It

is synthesized intracellularly inside the human body

using tyrosine as the fundamental building block. Its

role as an antioxidant is well established so it is

essential for health of all tissues and organs. (Soni S 24

et al in 2012) has shown that cells and tissues that

are metabolically active like heart, immune system,

gingiva require CoQ in highest amount. Topical

administration to the gingiva as a sole treatment may

decrease GCF flow and probing depths and improve

clinical gingival attachment. CoQ supplementation 10

has been beneficial to patients at risk of periodontal 25

diseases especially diabetics.

Simvastatin (SMV)-It is a new locally delivered

drug of class statins, is a specific competitive

inhibitor of 3-hydroxy-2-methyl-glutaryl coenzyme

A reductase. Statins, besides having lipid-lowering

abilities,.Studies have shown its pleiotropic effects

in periodontal therapy like host modulation and 26

bone regeneration .

HERBS AS LOCAL DRUG DELIVERY FOR

PERIODONTITIS

Eucalyptus extract: Ethanol extracts (60%

ethanol) from Euclyptus globulus leaves reportedly

possess antibacterial activity against various

bacteria, including oral bacteria. Moreover, 60%

ethanol extracts from the E. globulus leaf displayed



156

a n t i b a c t e r i a l a c t i v i t y a g a i n s t s e v e r a l

p e r i o d o n t o p a t h i c b a c t e r i a , i n c l u d i n g

Porphyromonas gingivalis and Prevotella

intermedia. In particular, among periodontopathic

bacteria, the growth of P. gingivalis was strongly

inhibited even with a low concentration (10 mg/ml) 27

of eucalyptus extracts.

Neem Leaf: Exract of neem leaf helps to reduce the

bacteria and plaque that causes progression of

periodontitis. Bioactive materials found in neem

leads to the presence of gallotannins during the early

stages of plaque formation that could effectively

reduce the number of bacteria available for binding

to the tooth surface by increasing their physical

removal from the oral cavity through aggregate

formation. Gallotannins extract also known to cause

inhibition of glucosyl transferase activity and

reduced bacterial adhesion to saliva coated

hydroxyappetite, suggesting its potential of having 28

antiplaque activity. A study was done to evaluate

the effectiveness of neem leaf extract against

plaque formation in males between the age group of

20–30 years over a period of 6 weeks. The results of

the study suggested that the gel containing neem

extract has significantly reduced the plaque index 29

and bacterial count than that of the control group.

Blood root: Also known by the name of Sanguinaria

Canadensis. It is well known for its alkaloid nature

that has shown to inhibit growth of bacteria causing

periodontitis. This herb is also included in

toothpastes and mouthwashes, it can reduce

inflammation and prevent deepening of periodontal 29

pockets, thereby preventing bone loss & tooth loss.

Chamomile: It belongs to plant of family

Asteraceae. With its anti-inflammatory and

antibacterial properties, chamomile helps in

reducing the inflammation in periodontal tissues 30

and reduces the bacterial load in the oral cavity.

Green tea (Camellia sinensis): It has received

considerable attention because of its numerable

scientifically proven health benefits attributable to

the presence of various polyphenols that include

epigallocatechin gallate (EGCG), epigallocatechin,

gallocatechin, gallocatechin gallate, epicatechin and

epicatechin gallate. Green tea catechins have also

been shown to be effective in the prevention and

treatment of periodontal disease and dental caries 31

due to their anti-microbial activity.

LOCAL DELIVERY OF GROWTH FACTORS

Platelet-derived growth factor (PDGF), vascular

endothelial growth factor (VEGF), and pyridinoline

cross-linked carboxyterminal telopeptide of Type I

collagen (ICTP) are mediators involved in

mitogenesis, angiogenesis, and bone turnover.

These mediators are essential for wound

regeneration of periodontal tissues. Growth factors

such as PDGF can stimulate cells involved in

periodontal regeneration and enhance periodontal

wound healing and regeneration. Studies have been

done on the effect of the local delivery of PDGF-BB

when combined with reconstructive periodontal

surgery on local wound fluid (WF) levels of PDGF-

AB, vascular endothelial growth factor (VEGF),

and bone collagen telopeptide (ICTP) in humans 32

with advanced periodontitis.

CONCLUSION

On the basis of available evidence, the use of local

drug delivery in periodontal pocket can improve the

periodontal health. However these drugs fail to

completely replace the conventional scaling and

root planning. Thus use of these drugs as

monotherapy is still controversial for improvement

of periodontal parameters. When compared to



157

systemic antimicrobials the risk of developing

resistant bacterial strains is less. Also the controlled

release properties of local drug delivery are

beneficial in maintaining localized lesions. From the

advancements in periodontal drug delivery systems

Nanodentistry will make possible the maintenance

of comprehensive oral health by employing

nanomaterials, biotechnology, including tissue

engineering and dental nanorobotics. Although this

technology is at an early stage, it has already made a

significant clinical and commercial impact.

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Competing interest / Conflict of interest The author(s) have no competing interests for financial support, publication of this research, patents and royalties through this collaborative research. All authors were equally involved in discussed research work. There is no financial conflict with the subject matter discussed in the manuscript.Source of support: NIL

Copyright © 2014 JPMCP. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dr Jagjit Singh - Jpmcp · The primary role of bacteria in the etiology of periodontal diseases is unequivocal. Despite of various treatment modalities, yet traditional mechanical